Parkinson's disease pathophysiology: Difference between revisions

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{{Parkinson's disease}}
{{Parkinson's disease}}


{{CMG}}
{{CMG}}  {{AE}} {{Fs}}


==Overview==
==Overview==
The underlying [[pathophysiology]] of [[Parkinson's disease|Parkinson disease]] is [[dopamine]] depletion. Reduced number of [[dopaminergic]] [[neurons]] lead to increased inhibition of [[thalamus]] and as a result, decrease excitation of [[Cortex|brain cortex]], causing [[bradykinesia]]. pathologic [[hallmark]] of [[Parkinson's disease|PD]] is [[Lewy body|lewy bodies]] which are round [[cytoplasmic]] [[eosinophilic]] inclusions. This disease can have so many triggers ( Protein misfolding, Defective proteolysis, Mitochondrial dysfunction, Oxidative stress, Iron metabolism and Immunologic and inflammatory mechanisms) but the main etiology of neuronal degeneration is either apoptosis or necrosis.


==Pathophysiology==
==Pathophysiology==
In the brain the direct pathway facilitates movement and the indirect pathway inhibits movement, thus the loss of these cells leads to a hypokinetic movement disorder.  The lack of [[dopamine]] results in increased inhibition of the ventral lateral nucleus of the thalamus, which sends excitatory projections to the motor cortex, thus leading to [[hypokinesia]].


There are four major dopamine pathways in the brain; the nigrostriatal pathway, referred to above, mediates movement and is the most conspicuously affected in early Parkinson's disease. The other pathways are the mesocortical, the mesolimbic, and the tuberoinfundibular. These pathways are associated with, respectively: volition and emotional responsiveness; desire, initiative, and reward; and sensory processes and maternal behavior. Disruption of dopamine along the non-striatal pathways likely explains much of the neuropsychiatric pathology associated with Parkinson's disease.
===Physiology===


The mechanism by which the brain cells in Parkinson's are lost may consist of an abnormal accumulation of the protein [[alpha-synuclein]] bound to ubiquitin in the damaged cells. The [[alpha-synuclein]]-ubiquitin complex cannot be directed to the proteosome. This [[protein]] accumulation forms proteinaceous cytoplasmic inclusions called [[Lewy bodies]]. Latest research on pathogenesis of disease has shown that the death of dopaminergic neurons by alpha-synuclein is due to a defect in the machinery that transports proteins between two major cellular organelles — the endoplasmic reticulum (ER) and the Golgi apparatus. Certain proteins like Rab1 may reverse this defect caused by alpha-synuclein in animal models.<ref>"Parkinson's Disease Mechanism Discovered," [http://www.hhmi.org/news/lindquist20060622.html HHMI Research News] June 22, 2006.</ref>
*The [[substantia nigra]] ([[Substantia nigra|SN]]), [[striatum]] ([[Caudate nucleus|caudate]] and [[putamen]]), [[globus pallidus]] ([[Globus pallidus|GP]]), [[subthalamic nucleus]] ([[Subthalamic nucleus|STN]]) and [[thalamus]] contribute with each other to make the [[extrapyramidal system]] or [[basal ganglia]].
*The impulses from [[hippocampus]], [[amygdala]] and prefrontal supplementary motor area to the [[basal ganglia]] are [[Excitatory synapse|excitatory]] mediated by [[glutamate]].
*The major [[dopaminergic]] [[neurons]] are in [[substantia nigra]] and are responsible for [[dopaminergic]] input of [[striatum]]. The striatal output is [[Inhibitory synapses|inhibitory]] ([[GABA]]) despite the [[Excitatory synapse|excitatory]] ([[glutamate]]) output of [[Subthalamic nucleus|STN]] to the [[globus pallidus]] (medial and lateral).
*There are 5 [[dopamine receptors]] (D1_D5) which are in [[basal ganglia]] and [[limbic system]]. [[D1 receptor|D1]] and [[D2 receptor|D2]] are mostly found in the dorsal [[striatum]] (motor) and are activated through [[dopaminergic]] pathway from [[Substantia nigra|SNc]], as a result, they are very important in the [[pathophysiology]] of Parkinson disease. D3 and D4 are located mostly in [[Mesolimbic system|mesolimbic]] or emotional part of the [[brain]] and D5 in [[hippocampus]]/[[hypothalamus]] area.<ref name="pmid11052222">{{cite journal |vauthors=Gerfen CR |title=Molecular effects of dopamine on striatal-projection pathways |journal=Trends Neurosci. |volume=23 |issue=10 Suppl |pages=S64–70 |date=October 2000 |pmid=11052222 |doi= |url=}}</ref>


Excessive accumulations of iron, which are toxic to nerve cells, are also typically observed in conjunction with the protein inclusions.  Iron and other transition metals such as copper bind to [[neuromelanin]] in the affected neurons of the [[substantia nigra]]. So, [[neuromelanin]] may be acting as a protective agent.  Alternately, neuromelanin (an electronically active semiconductive polymer) may play some other role in neurons.<ref>{{cite journal | author = McGinness J, Corry P, Proctor P | title = Amorphous semiconductor switching in melanins. | journal = Science | volume = 183 | issue = 127 | pages = 853-5 | year = 1974 | pmid = 4359339 | url=http://www.drproctor.com/os/amorphous.htm | format=Reprint}}</ref>  That is, coincidental excessive accumulation of transition metals, etc. on [[neuromelanin]] may figure in the differential dropout of pigmented neurons in Parkinsonism.  The most likely mechanism is generation of [[reactive oxygen species]].<ref name="Jenner1998">{{cite journal | author = Jenner P | title = Oxidative mechanisms in nigral cell death in Parkinson's disease. | journal = Mov Disord | volume = 13 Suppl 1 | issue = | pages = 24-34 | year =1998 | pmid = 9613715}}</ref>
===Phatogenesis===


Iron induces aggregation of synuclein by oxidative mechanisms.<ref>{{cite journal | author = Kaur D, Andersen J | title = Ironing out Parkinson's disease: is therapeutic treatment with iron chelators a real possibility? | journal = Aging Cell | volume = 1 | issue = 1 | pages = 17-21 | year = 2002 | pmid = 12882349 | url=http://www.blackwell-synergy.com/doi/pdf/10.1046/j.1474-9728.2002.00001.x | format=PDF}}</ref> Similarly, dopamine and the byproducts of dopamine production enhance alpha-synuclein aggregation. The precise mechanism whereby such aggregates of alpha-synuclein damage the cells is not known. The aggregates may be merely a normal reaction by the cells as part of their effort to correct a different, as-yet unknown, insult. Based on this mechanistic hypothesis, a [[Genetically modified organism|transgenic mouse model]] of Parkinson's has been generated by introduction of human wild-type α-synuclein into the mouse genome under control of the [[Platelet-derived growth factor|platelet-derived-growth factor]]-β promoter.<ref>{{cite journal |author=Masliah E, Rockenstein E, Veinbergs I, ''et al'' |title=Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders |journal=Science |volume=287 |issue=5456 |pages=1265-9 |year=2000 |pmid=10678833 |doi=}}</ref>
*The underlying [[pathophysiology]] of [[Parkinson's disease|Parkinson disease]] is [[dopamine]] depletion. In the course of the disease [[dopamine]] depletion of [[nigrostriatal pathway]] will lead to denervation hypersensitivity and increasing number of [[D2 receptor|D2]] receptors in dorsal [[putamen]].<ref name="pmid15509741">{{cite journal |vauthors=Bamford NS, Robinson S, Palmiter RD, Joyce JA, Moore C, Meshul CK |title=Dopamine modulates release from corticostriatal terminals |journal=J. Neurosci. |volume=24 |issue=43 |pages=9541–52 |date=October 2004 |pmid=15509741 |doi=10.1523/JNEUROSCI.2891-04.2004 |url=}}</ref>
*There are two pathways in this system: Direct and indirect pathway.
*Indirect pathway starts with [[inhibition]] of [[striatum]] via [[D2 receptor]] which in turn [[Inhibition|inhibits]] [[neurons]] of lateral [[Globus pallidus|GP]] by [[GABA]] which [[Inhibition|inhibits]] the inhibition of [[Subthalamic nucleus|STN]] by lateral [[Globus pallidus|GP]]. [[Subthalamic nucleus|STN]] provides [[Excitatory synapse|excitatory]] action on [[Globus pallidus|GP]] internal and [[Substantia nigra|SNr]] via [[glutamate]]. [[Globus pallidus|GPi]] inhibit [[thalamus]] by [[GABA]] but [[cortex]] input from [[thalamus]] is [[Excitatory synapse|excitatory]].
*Direct pathway starts with [[excitation]] of [[striatum]] by stimulation of [[D1 receptor|D1 receptors]], then [[striatum]] inhibits [[Globus pallidus|GP]] internal and [[Substantia nigra|SNr]] by [[GABA]] directly. Reduced number of [[dopaminergic]] [[neurons]] lead to increased inhibition of [[thalamus]] and as a result, decrease excitation of [[Cortex|brain cortex]], causing [[bradykinesia]].<ref name="pmid16830313">{{cite journal |vauthors=Gatev P, Darbin O, Wichmann T |title=Oscillations in the basal ganglia under normal conditions and in movement disorders |journal=Mov. Disord. |volume=21 |issue=10 |pages=1566–77 |date=October 2006 |pmid=16830313 |doi=10.1002/mds.21033 |url=}}</ref>
*Our [[brain]] has some compensatory mechanism fighting [[dopamine]] depletion. It can increase the synthesis of [[dopamine]], [[gap junctions]] and the number of [[D2 receptor|D2 receptors]].<ref name="pmid11052221">{{cite journal |vauthors=Calabresi P, Centonze D, Bernardi G |title=Electrophysiology of dopamine in normal and denervated striatal neurons |journal=Trends Neurosci. |volume=23 |issue=10 Suppl |pages=S57–63 |date=October 2000 |pmid=11052221 |doi= |url=}}</ref><ref name="pmid12464455">{{cite journal |vauthors=Moore H, Grace AA |title=A role for electrotonic coupling in the striatum in the expression of dopamine receptor-mediated stereotypies |journal=Neuropsychopharmacology |volume=27 |issue=6 |pages=980–92 |date=December 2002 |pmid=12464455 |doi=10.1016/S0893-133X(02)00383-4 |url=}}</ref> It can also reduce the uptake of [[dopamine]] from synaptic space.<ref name="pmid16081470">{{cite journal |vauthors=Adams JR, van Netten H, Schulzer M, Mak E, Mckenzie J, Strongosky A, Sossi V, Ruth TJ, Lee CS, Farrer M, Gasser T, Uitti RJ, Calne DB, Wszolek ZK, Stoessl AJ |title=PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation |journal=Brain |volume=128 |issue=Pt 12 |pages=2777–85 |date=December 2005 |pmid=16081470 |doi=10.1093/brain/awh607 |url=}}</ref>
*The main [[pathology]] seen in [[Parkinson disease|PD]] patients is neuronal loss, depigmentation and [[gliosis]] which are mostly seen in the [[locus ceruleus]] and [[substantia nigra]]. The normal number of pigmented neurons in [[Substantia nigra|SN]] in a normal individual is about 550,000, but in patient with [[Parkinson's disease|PD]] in can decrease as much as 66%.<ref name="pmid2010756">{{cite journal |vauthors=Pakkenberg B, Møller A, Gundersen HJ, Mouritzen Dam A, Pakkenberg H |title=The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson's disease estimated with an unbiased stereological method |journal=J. Neurol. Neurosurg. Psychiatry |volume=54 |issue=1 |pages=30–3 |date=January 1991 |pmid=2010756 |pmc=1014294 |doi= |url=}}</ref>
*In the normal aging process, neuronal loss occurs in the dorsal tier of [[Substantia nigra|SN]] pars compacta and the most of [[dopamine]] depletion is seen in [[caudate nucleus]]. But in Parkinson, loss of [[dopaminergic]] neurons occurs predominantly in ventrolateral portion of the [[Substantia nigra|SN]].<ref name="pmid15726582">{{cite journal |vauthors=Porritt M, Stanic D, Finkelstein D, Batchelor P, Lockhart S, Hughes A, Kalnins R, Howells D |title=Dopaminergic innervation of the human striatum in Parkinson's disease |journal=Mov. Disord. |volume=20 |issue=7 |pages=810–8 |date=July 2005 |pmid=15726582 |doi=10.1002/mds.20399 |url=}}</ref><ref name="pmid1933245">{{cite journal |vauthors=Fearnley JM, Lees AJ |title=Ageing and Parkinson's disease: substantia nigra regional selectivity |journal=Brain |volume=114 ( Pt 5) |issue= |pages=2283–301 |date=October 1991 |pmid=1933245 |doi= |url=}}</ref>
*The other sites of the [[brain]] which are influenced by [[Parkinson's disease|PD]] are internal segment of the [[globus pallidus]], center median parafascicular complex, pedunculopontine tegmental nucleus, glutamatergic caudal intralaminar thalamic nuclei and [[hippocampus]].<ref name="pmid10716254">{{cite journal |vauthors=Henderson JM, Carpenter K, Cartwright H, Halliday GM |title=Degeneration of the centré median-parafascicular complex in Parkinson's disease |journal=Ann. Neurol. |volume=47 |issue=3 |pages=345–52 |date=March 2000 |pmid=10716254 |doi= |url=}}</ref><ref name="pmid12815657">{{cite journal |vauthors=Camicioli R, Moore MM, Kinney A, Corbridge E, Glassberg K, Kaye JA |title=Parkinson's disease is associated with hippocampal atrophy |journal=Mov. Disord. |volume=18 |issue=7 |pages=784–90 |date=July 2003 |pmid=12815657 |doi=10.1002/mds.10444 |url=}}</ref>
*PD may have so many triggers but the main etiology of neuronal degeneration is either apoptosis or necrosis.<ref name="pmid16823471">{{cite journal |vauthors=Savitt JM, Dawson VL, Dawson TM |title=Diagnosis and treatment of Parkinson disease: molecules to medicine |journal=J. Clin. Invest. |volume=116 |issue=7 |pages=1744–54 |date=July 2006 |pmid=16823471 |pmc=1483178 |doi=10.1172/JCI29178 |url=}}</ref><ref name="pmid17372132">{{cite journal |vauthors=Lang AE |title=The progression of Parkinson disease: a hypothesis |journal=Neurology |volume=68 |issue=12 |pages=948–52 |date=March 2007 |pmid=17372132 |doi=10.1212/01.wnl.0000257110.91041.5d |url=}}</ref><ref name="pmid25071440">{{cite journal |vauthors=Atkin G, Paulson H |title=Ubiquitin pathways in neurodegenerative disease |journal=Front Mol Neurosci |volume=7 |issue= |pages=63 |date=2014 |pmid=25071440 |pmc=4085722 |doi=10.3389/fnmol.2014.00063 |url=}}</ref>


<gallery>
====Protein misfolding====
Image:DA-loops in PD.jpg|Dopaminergic pathways of the human brain in normal condition (left) and Parkinson's disease (right). Red Arrows indicate suppression of the target, blue arrows indicate stimulation of target structure.
</gallery>


The symptoms of Parkinson's disease result from the loss of pigmented [[dopamine]]-secreting (dopaminergic) cells, secreted by the same cells, in the [[substantia nigra|pars compacta]] region of the [[substantia nigra]] (literally "black substance"). These neurons project to the [[striatum]] and their loss leads to alterations in the activity of the neural circuits within the basal ganglia that regulate movement, in essence an inhibition of the [[direct pathway]] and excitation of the [[indirect pathway]].
*One of the main underlying cause of [[Parkinson's disease|PD]] is [[mutation]] in the gene of [[alpha-synuclein]] protein which is abundant in the [[CNS]].
*Its function is thought to be involved in [[synaptic]] function and [[plasticity]].<ref name="pmid12951565">{{cite journal |vauthors=Maries E, Dass B, Collier TJ, Kordower JH, Steece-Collier K |title=The role of alpha-synuclein in Parkinson's disease: insights from animal models |journal=Nat. Rev. Neurosci. |volume=4 |issue=9 |pages=727–38 |date=September 2003 |pmid=12951565 |doi=10.1038/nrn1199 |url=}}</ref><ref name="pmid26790375">{{cite journal |vauthors=Calo L, Wegrzynowicz M, Santivañez-Perez J, Grazia Spillantini M |title=Synaptic failure and α-synuclein |journal=Mov. Disord. |volume=31 |issue=2 |pages=169–77 |date=February 2016 |pmid=26790375 |doi=10.1002/mds.26479 |url=}}</ref>
*This [[Mutation|mutations]] lead to unfold [[alpha-synuclein]] and aggregation of insoluble [[protein]] and [[neuronal]] damage.
*[[Lewy body|Lewy bodies]] which are characteristic of [[Parkinson's disease|PD]] are mostly build from [[alpha-synuclein]] [[protein]].<ref name="pmid9278044">{{cite journal |vauthors=Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M |title=Alpha-synuclein in Lewy bodies |journal=Nature |volume=388 |issue=6645 |pages=839–40 |date=August 1997 |pmid=9278044 |doi=10.1038/42166 |url=}}</ref>


===Genetic===
====Defective proteolysis====


In recent years, a number of specific genetic mutations causing Parkinson's disease have been discovered, including in certain populations ([[Contursi]], Italy). These account for a small minority of cases of Parkinson's disease. Somebody who has Parkinson's disease is more likely to have relatives that also have Parkinson's disease. However, this does not mean that the disorder has been passed on genetically.  
*There are three pathways which control the [[protein]] [[homeostasis]] in cells: Molecular chaperons, the ubiquitin-proteasome system and autophagy-lysosomal pathway.
*[[Alpha-synuclein|Alpha synuclein]] processing is done by all of this three mechanisms and defect in any of them can cause aggregation of this [[protein]] and [[neuronal]] death.<ref name="pmid23580245">{{cite journal |vauthors=Lim KL, Zhang CW |title=Molecular events underlying Parkinson's disease - an interwoven tapestry |journal=Front Neurol |volume=4 |issue= |pages=33 |date=2013 |pmid=23580245 |pmc=3619247 |doi=10.3389/fneur.2013.00033 |url=}}</ref><ref name="pmid23580333">{{cite journal |vauthors=Dehay B, Martinez-Vicente M, Caldwell GA, Caldwell KA, Yue Z, Cookson MR, Klein C, Vila M, Bezard E |title=Lysosomal impairment in Parkinson's disease |journal=Mov. Disord. |volume=28 |issue=6 |pages=725–32 |date=June 2013 |pmid=23580333 |pmc=5131721 |doi=10.1002/mds.25462 |url=}}</ref><ref name="pmid24211851">{{cite journal |vauthors=Ghavami S, Shojaei S, Yeganeh B, Ande SR, Jangamreddy JR, Mehrpour M, Christoffersson J, Chaabane W, Moghadam AR, Kashani HH, Hashemi M, Owji AA, Łos MJ |title=Autophagy and apoptosis dysfunction in neurodegenerative disorders |journal=Prog. Neurobiol. |volume=112 |issue= |pages=24–49 |date=January 2014 |pmid=24211851 |doi=10.1016/j.pneurobio.2013.10.004 |url=}}</ref>


Genetic forms that have been identified include:
====Mitochondrial dysfunction====
:''external links in this section are to [[OMIM]]''


{| class="wikitable"
*The [[drug]] 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an [[Analog (chemistry)|analog]] of mepridine is found to be associated with [[Parkinson's disease|PD]].
| '''Type''' || '''OMIM''' || '''[[Locus (genetics)|Locus]]''' || '''Details'''
*The [[oxidation]] of this drug produces 1-methyl-4-phenylpyridium which inhibits complex one of mitochondria and result in [[cell]] damage.
|-  
*Studies showed that the activity of this complex is decreased in [[Parkinson's disease|PD]] patients.<ref name="pmid15377875">{{cite journal |vauthors=Przedborski S, Tieu K, Perier C, Vila M |title=MPTP as a mitochondrial neurotoxic model of Parkinson's disease |journal=J. Bioenerg. Biomembr. |volume=36 |issue=4 |pages=375–9 |date=August 2004 |pmid=15377875 |doi=10.1023/B:JOBB.0000041771.66775.d5 |url=}}</ref><ref name="pmid22446186">{{cite journal |vauthors=Selvaraj S, Sun Y, Watt JA, Wang S, Lei S, Birnbaumer L, Singh BB |title=Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling |journal=J. Clin. Invest. |volume=122 |issue=4 |pages=1354–67 |date=April 2012 |pmid=22446186 |pmc=3314472 |doi=10.1172/JCI61332 |url=}}</ref><ref name="pmid2566813">{{cite journal |vauthors=Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD |title=Mitochondrial complex I deficiency in Parkinson's disease |journal=Lancet |volume=1 |issue=8649 |pages=1269 |date=June 1989 |pmid=2566813 |doi= |url=}}</ref>
| ''PARK1'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=168601 OMIM #168601] || 4q21 || caused by mutations in the ''[[SNCA]]'' gene, which codes for the [[protein]] [[alpha-synuclein]].  PARK1 causes [[autosomal dominant]] Parkinson disease.  So-called ''PARK4'' ([http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=605543 OMIM #605543]) is probably caused by triplication of ''SNCA''.<ref>{{cite journal |author=Singleton AB, Farrer M, Johnson J, ''et al'' |title=alpha-Synuclein locus triplication causes Parkinson's disease |journal=Science |volume=302 |issue=5646 |pages=841 |year=2003 |pmid=14593171 |doi=10.1126/science.1090278}}</ref>
|-
| ''PARK2'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602544 OMIM *602544] || 6q25.2-q27 || caused by mutations in protein [[Parkin (ligase)|parkin]].  Parkin mutations may be one of the most common known genetic causes of early-onset Parkinson disease.  In one study, of patients with onset of Parkinson disease prior to age 40 (10% of all PD patients), 18% had parkin mutations, with 5% [[homozygous]] mutations.<ref>{{cite journal | author=Poorkaj P ''et al.'' | title=''parkin'' mutation analysis in clinic patients with early-onset Parkinson's disease | journal=American Journal of Medical Genetics Part A | year=2004 | volume=129A |
issue=1 | pages= 44&ndash;50 | url=http://www3.interscience.wiley.com/cgi-bin/abstract/109062750/ABSTRACT?CRETRY=1&SRETRY=0}}</ref> Patients with an [[autosomal recessive]] family history of parkinsonism are much more likely to carry parkin mutations if age at onset is less than 20 (80% vs. 28% with onset over age 40).<ref>{{cite journal | author=Ebba Lohmann ''et al.'' | title=How much phenotypic variation can be attributed to parkin genotype? | journal=Annals of Neurology | year=2003 | volume=54 | issue=2 | pages= 176&ndash;185|url=http://www3.interscience.wiley.com/cgi-bin/abstract/104536414/ABSTRACT | pmid = 12891670}}</ref>Patients with [[parkin]] mutations (PARK2) do not have Lewy bodies.  Such patients develop a syndrome that closely resembles the sporadic form of PD; however, they tend to develop symptoms at a much younger age.
|-  
| ''PARK3'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602404 OMIM %602404] || 2p13 || autosomal dominant, only described in a few kindreds.
|-  
| ''PARK5'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191342 OMIM +191342]  || 4p14 || caused by mutations in the ''UCHL1'' gene which codes for the protein [[ubiquitin carboxy-terminal hydrolase L1]]
|-
| ''PARK6'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=605909 OMIM #605909] || 1p36 || caused by mutations in ''PINK1'' ([http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=605909 OMIM *608309]) which codes for the protein [[PTEN-induced putative kinase 1]].
|-
| ''[[PARK7]]'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606324 OMIM #606324] || 1p36 || caused by mutations in [[PARK7|DJ-1]] ([http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602533 OMIM 602533])
|-
| ''PARK8'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607060 OMIM #607060] || 12q12 || caused by mutations in [[LRRK2]] which codes for the protein [[dardarin]].  ''In vitro'', mutant LRRK2 causes protein aggregation and cell death, possibly through an interaction with parkin.<ref>{{cite journal | author=Smith WW ''et al.'' | title=Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration | journal=[[Proceedings of the National Academy of Sciences of the United States of America]] | year=2005 | volume=102 | issue=51 | pages= 18676&ndash;18681 | url=http://www.pnas.org/cgi/content/abstract/102/51/18676 | pmid = 16352719}}</ref> LRRK2 mutations, of which the most common is G2019S, cause autosomal dominant Parkinson disease, with a [[penetrance]] of nearly 100% by age 80.<ref>{{cite journal |author=Kachergus J, Mata IF, Hulihan M, ''et al'' |title=Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations |journal=Am. J. Hum. Genet. |volume=76 |issue=4 |pages=672-80 |year=2005 |pmid=15726496 |doi=10.1086/429256}}</ref> G2019S is the most common known genetic cause of Parkinson disease, found in 1-6% of U.S. and European PD patients.<ref>{{cite journal |author=Brice A |title=Genetics of Parkinson's disease: LRRK2 on the rise |journal=Brain |volume=128 |issue=Pt 12 |pages=2760-2 |year=2005 |url=http://brain.oxfordjournals.org/cgi/content/extract/128/12/2760 |pmid=16311269 |doi=10.1093/brain/awh676}}
</ref> It is especially common in Ashkenazi Jewish patients, with a prevalence of 29.7% in familial cases and 13.3% in sporadic.<ref>{{cite journal | author = Ozelius L, Senthil G, Saunders-Pullman R, ''et al'' | title = LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. | journal = N Engl J Med | volume = 354 | issue = 4 | pages = 424-5 | year = 2006 | pmid = 16436782}}</ref>
|-
| ''PARK9'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606693 OMIM #606693] || 1p36 ||  Caused by mutations in the ''ATP13A2'' gene, and also known as Kufor-Rakeb Syndrome.  PARK9 may be allelic to PARK6.
|-
| ''PARK10'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606852 OMIM %606852] || 1p || -
|-
| ''PARK11'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607688 OMIM %607688] || 2q36-37 ||  However, this gene locus has conflicting data, and may not have significance.
|-
| ''PARK12'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300557 OMIM %300557] || Xq21-q25 || -
|-
| ''PARK13'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=610297 OMIM #610297] || 2p12 ||  Caused by mutations in the ''HTRA2'' ([[HtrA serine peptidase 2]]) gene.
|}


===Toxins===
====Oxidative stress====


One theory holds that the disease may result in many or even most cases from the combination of a genetically determined vulnerability to environmental [[toxin]]s along with exposure to those toxins.<ref>{{cite journal |author=Di Monte DA, Lavasani M, Manning-Bog AB |title=Environmental factors in Parkinson's disease |journal=Neurotoxicology |volume=23 |issue=4-5 |pages=487-502 |year=2002 |pmid=12428721 |doi=}}</ref>  This hypothesis is consistent with the fact that Parkinson's disease is not distributed homogeneously throughout the population: rather, its incidence varies geographically. It would appear that incidence varies by time as well, for although the later stages of untreated PD are distinct and readily recognizable, the disease was not remarked upon until the beginnings of the Industrial Revolution, and not long thereafter become a common observation in clinical practice. The toxins most strongly suspected at present are certain [[pesticide]]s and transition-series metals such as manganese or iron, especially those that generate [[reactive oxygen species]],<ref name="Jenner1998">{{cite journal |author=Jenner P |title=Oxidative mechanisms in nigral cell death in Parkinson's disease |journal=Mov. Disord. |volume=13 Suppl 1 |issue= |pages=24-34 |year=1998 |pmid=9613715 |doi=}}</ref><ref>{{cite journal |author=Chiueh CC, Andoh T, Lai AR, Lai E, Krishna G |title=Neuroprotective strategies in Parkinson's disease: protection against progressive nigral damage induced by free radicals |journal=Neurotoxicity research |volume=2 |issue=2-3 |pages=293-310 |year=2000 |pmid=16787846 |doi=}}</ref>
*[[Reactive oxygen species]] including [[hydrogen peroxide]], superoxide anions and hydroxyradicals are [[toxic]] to [[neurons]] and cause [[neuronal]] damage.
and or bind to [[neuromelanin]], as originally suggested by G.C. Cotzias.<ref>{{cite journal | author = Cotzias G | title = Manganese, melanins and the extrapyramidal system. | journal = J Neurosurg | volume = 24 | issue = 1 | pages = Suppl:170-80 | year = 1966 | pmid = 4955707}}</ref><ref>{{cite journal | author = Barbeau A | title = Manganese and extrapyramidal disorders (a critical review and tribute to Dr. George C. Cotzias). | journal = Neurotoxicology | volume = 5 | issue = 1 | pages = 13-35 | year = 1984 | pmid = 6538948}}</ref>.  In the Cancer Prevention Study II Nutrition Cohort, a longitudinal investigation, individuals who were exposed to pesticides had a 70% higher incidence of PD than individuals who were not exposed<ref>{{cite journal | author = Ascherio A, Chen H, Weisskopf M, ''et al'' | title = Pesticide exposure and risk for Parkinson's disease. | journal = Ann Neurol | volume = 60 | issue = 2 | pages = 197-203 | year = 2006 | pmid = 16802290}}</ref>.
*They interact with [[membrane lipids]] and cause [[lipid peroxidation]] which can be seen in [[substantia nigra]] of [[Parkinson's disease|PD]] patients.<ref name="pmid15155938">{{cite journal |vauthors=Greenamyre JT, Hastings TG |title=Biomedicine. Parkinson's--divergent causes, convergent mechanisms |journal=Science |volume=304 |issue=5674 |pages=1120–2 |date=May 2004 |pmid=15155938 |doi=10.1126/science.1098966 |url=}}</ref><ref name="pmid14645467">{{cite journal |vauthors=Sherer TB, Betarbet R, Testa CM, Seo BB, Richardson JR, Kim JH, Miller GW, Yagi T, Matsuno-Yagi A, Greenamyre JT |title=Mechanism of toxicity in rotenone models of Parkinson's disease |journal=J. Neurosci. |volume=23 |issue=34 |pages=10756–64 |date=November 2003 |pmid=14645467 |doi= |url=}}</ref>
*They can also cause protein misfolding by attacking disulfide isomerase through [[nitric oxide]]. Disulfide isomerase is a [[chaperone]] preventing the aggregation of [[proteins]].<ref name="pmid16724068">{{cite journal |vauthors=Uehara T, Nakamura T, Yao D, Shi ZQ, Gu Z, Ma Y, Masliah E, Nomura Y, Lipton SA |title=S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration |journal=Nature |volume=441 |issue=7092 |pages=513–7 |date=May 2006 |pmid=16724068 |doi=10.1038/nature04782 |url=}}</ref>


[[MPTP]] is used as a model for Parkinson's as it can rapidly induce parkinsonian symptoms in human beings and other animals, of any age.  MPTP was notorious for a string of Parkinson's disease cases in California in 1982 when it contaminated the illicit production of the synthetic opiate [[MPPP]].  Its toxicity likely comes from generation of [[reactive oxygen species]] through tyrosine hydroxylation.<ref>{{cite journal | author = Chiueh C, Wu R, Mohanakumar K, Sternberger L, Krishna G, Obata T, Murphy D | title = ''In vivo'' generation of hydroxyl radicals and MPTP-induced dopaminergic toxicity in the basal ganglia. | journal = Ann N Y Acad Sci | volume = 738 | issue = | pages = 25-36 | year = 1994 |pmid = 7832434}}</ref>
====Iron metabolism====


Other toxin-based models employ PCBs,<ref>{{cite news
*Studies showed that impaired [[iron metabolism]] leads to increase amount of [[iron]] in [[substantia nigra]] of [[Parkinson's disease|PD]] patients.
  |first=Leslie
*One of the underlying [[etiology]] of [[iron]] accommodation in [[Neuron|neuronal cells]] is the absence of [[tau protein]].<ref name="pmid17515544">{{cite journal |vauthors=Oakley AE, Collingwood JF, Dobson J, Love G, Perrott HR, Edwardson JA, Elstner M, Morris CM |title=Individual dopaminergic neurons show raised iron levels in Parkinson disease |journal=Neurology |volume=68 |issue=21 |pages=1820–5 |date=May 2007 |pmid=17515544 |doi=10.1212/01.wnl.0000262033.01945.9a |url=}}</ref><ref name="pmid22266337">{{cite journal |vauthors=Dusek P, Jankovic J, Le W |title=Iron dysregulation in movement disorders |journal=Neurobiol. Dis. |volume=46 |issue=1 |pages=1–18 |date=April 2012 |pmid=22266337 |doi=10.1016/j.nbd.2011.12.054 |url=}}</ref><ref name="pmid22286308">{{cite journal |vauthors=Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, Wong BX, Adlard PA, Cherny RA, Lam LQ, Roberts BR, Volitakis I, Egan GF, McLean CA, Cappai R, Duce JA, Bush AI |title=Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export |journal=Nat. Med. |volume=18 |issue=2 |pages=291–5 |date=January 2012 |pmid=22286308 |doi=10.1038/nm.2613 |url=}}</ref>
  |last=Orr
  |title=PCBs, fungicide open brain cells to Parkinson's assault
  |date=February 10, 2005
  |publisher=[[Medical News Today]]
  |url=http://www.medicalnewstoday.com/medicalnews.php?newsid=19791
}}</ref> [[paraquat]]<ref>{{cite journal |author=Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA |title=The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein |journal=J. Biol. Chem. |volume=277 |issue=3 |pages=1641-4 |year=2002 |pmid=11707429 |doi=10.1074/jbc.C100560200 | url=http://www.jbc.org/cgi/content/full/277/3/1641}}</ref> (a herbicide) in combination with maneb (a fungicide)<ref>{{cite journal |author=Thiruchelvam M, Richfield EK, Baggs RB, Tank AW, Cory-Slechta DA |title=The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson's disease |journal=J. Neurosci. |volume=20 |issue=24 |pages=9207-14 |year=2000 |pmid=11124998 |url=http://www.jneurosci.org/cgi/content/full/20/24/9207
}}</ref> [[rotenone]]<ref>{{cite journal |author=Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT |title=Chronic systemic pesticide exposure reproduces features of Parkinson's disease |journal=Nat. Neurosci. |volume=3 |issue=12 |pages=1301-6 |year=2000 |pmid=11100151 |doi=10.1038/81834}}</ref> (an insecticide), and specific organochlorine pesticides including dieldrin<ref>{{cite journal |author=Kitazawa M, Anantharam V, Kanthasamy AG |title=Dieldrin-induced oxidative stress and neurochemical changes contribute to apoptopic cell death in dopaminergic cells |journal=Free Radic. Biol. Med. |volume=31 |issue=11 |pages=1473-85 |year=2001 |pmid=11728820 |url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T38-44HSN76-P&_coverDate=12%2F01%2F2001&_alid=373422978&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4940&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=5a104ac89bd7948e14863371142a639a
}}</ref> and lindane.<ref>{{cite journal |author=Corrigan FM, Wienburg CL, Shore RF, Daniel SE, Mann D |title=Organochlorine insecticides in substantia nigra in Parkinson's disease |journal=J. Toxicol. Environ. Health Part A |volume=59 |issue=4 |pages=229-34 |year=2000 |pmid=10706031
  |url=http://journalsonline.tandf.co.uk/openurl.asp?genre=article&eissn=1087-2620&volume=59&issue=4&spage=229
}}</ref> Numerous studies have found an increase in PD in persons who consume rural well water; researchers theorize that water consumption is a proxy measure of pesticide exposure. In agreement with this hypothesis are studies which have found a dose-dependent an increase in PD in persons exposed to agricultural chemicals.


===Head trauma===
====Immunologic and inflammatory mechanisms====
Past episodes of head trauma are reported more frequently by sufferers than by others in the population.<ref name=Bower>{{cite journal |author=Bower JH, Maraganore DM, Peterson BJ, McDonnell SK, Ahlskog JE, Rocca WA |title=Head trauma preceding PD: a case-control study |journal=Neurology |volume=60 |issue=10 |pages=1610-5 |year=2003 |pmid=12771250 | url=http://www.neurology.org/cgi/content/abstract/60/10/1610}}</ref><ref>{{cite journal |author=Stern M, Dulaney E, Gruber SB, ''et al'' |title=The epidemiology of Parkinson's disease. A case-control study of young-onset and old-onset patients |journal=Arch. Neurol. |volume=48 |issue=9 |pages=903-7 |year=1991 |pmid=1953412  url=http://archneur.ama-assn.org/cgi/content/abstract/48/9/903}}</ref><ref name="Uryu2003">{{cite journal |author=Uryu K, Giasson BI, Longhi L, ''et al'' |title=Age-dependent synuclein pathology following traumatic brain injury in mice |journal=Exp. Neurol. |volume=184 |issue=1 |pages=214-24 |year=2003 |pmid=14637093 |doi=}}</ref>
A methodologically strong recent study<ref name=Bower/> found that those who have experienced a head injury are four times more likely to develop Parkinson’s disease than those who have never suffered a head injury. The risk of developing Parkinson’s increases eightfold for patients who have had head trauma requiring hospitalization, and it increases 11-fold for patients who have experienced severe head injury. The authors comment that since head trauma is a rare event, the contribution to PD incidence is slight. They express further concern that their results may be biased by recall, i.e., the PD patients because they reflect upon the causes of their illness, may remember head trauma better than the non-ill control subjects. These limitations were overcome recently by Tanner and colleagues,<ref>{{cite journal |author=Goldman SM, Tanner CM, Oakes D, Bhudhikanok GS, Gupta A, Langston JW |title=Head injury and Parkinson's disease risk in twins |journal=Ann. Neurol. |volume=60 |issue=1 |pages=65-72 |year=2006 |pmid=16718702 |doi=10.1002/ana.20882}}</ref> who found a similar risk of 3.8, with increasing risk associated with more severe injury and hospitalization.


===Drug-induced===
*There are some studies supporting the idea of [[Immunology|immunologic]] mechanisms causing [[Parkinson's disease|PD]].<ref name="pmid19296921">{{cite journal |vauthors=Hirsch EC, Hunot S |title=Neuroinflammation in Parkinson's disease: a target for neuroprotection? |journal=Lancet Neurol |volume=8 |issue=4 |pages=382–97 |date=April 2009 |pmid=19296921 |doi=10.1016/S1474-4422(09)70062-6 |url=}}</ref>
*In [[Parkinson's disease|PD]] patients there is elevated amounts of [[cyclooxygenase-2]] which is the rate limiting enzyme in [[Prostaglandin E|prostaglandin E2]] synthesis.<ref name="pmid12702778">{{cite journal |vauthors=Teismann P, Tieu K, Choi DK, Wu DC, Naini A, Hunot S, Vila M, Jackson-Lewis V, Przedborski S |title=Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=100 |issue=9 |pages=5473–8 |date=April 2003 |pmid=12702778 |pmc=154369 |doi=10.1073/pnas.0837397100 |url=}}</ref>
*[[Neuron|Neuronal cell]] death can also occur due to infiltration of [[CD4+ T cells]].<ref name="pmid19104149">{{cite journal |vauthors=Brochard V, Combadière B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay JM, Duyckaerts C, Flavell RA, Hirsch EC, Hunot S |title=Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease |journal=J. Clin. Invest. |volume=119 |issue=1 |pages=182–92 |date=January 2009 |pmid=19104149 |pmc=2613467 |doi=10.1172/JCI36470 |url=}}</ref>


[[Antipsychotics]], which are used to treat [[schizophrenia]] and psychosis, can induce the symptoms of Parkinson's disease (or parkinsonism) by lowering dopaminergic activity. Due to feedback inhibition, L-dopa can also eventually cause the symptoms of Parkinson's disease that it initially relieves. Dopamine agonists can also eventually contribute to Parkinson's disease symptoms by decreasing the sensitivity of dopamine receptors.
==Genetics==


==Associated Disorders==
*There are some evidence showing that there is an association between [[Parkinson's disease|PD]] and [[genetic]].
There are other disorders that are called ''[[Parkinson plus syndrome|Parkinson-plus diseases]]''. These include:
*This role is higher when Parkinson disease occurs in the individual younger than 50 years old.<ref name="pmid23389780">{{cite journal |vauthors=Singleton AB, Farrer MJ, Bonifati V |title=The genetics of Parkinson's disease: progress and therapeutic implications |journal=Mov. Disord. |volume=28 |issue=1 |pages=14–23 |date=January 2013 |pmid=23389780 |pmc=3578399 |doi=10.1002/mds.25249 |url=}}</ref>
*These studies also demonstrate that if a person has a first degree with [[Parkinson's disease|PD]], the risk of developing [[Parkinson's disease|PD]] is 2 to 3 times higher than normal population. Conversely, in 25 to 50 % of PD patients we can find at least one first degree having [[Parkinson's disease|PD]].<ref name="pmid8710070">{{cite journal |vauthors=Marder K, Tang MX, Mejia H, Alfaro B, Côté L, Louis E, Groves J, Mayeux R |title=Risk of Parkinson's disease among first-degree relatives: A community-based study |journal=Neurology |volume=47 |issue=1 |pages=155–60 |date=July 1996 |pmid=8710070 |doi= |url=}}</ref>


* [[Multiple system atrophy]] (MSA)
Some of specific genes involving in [[Parkinson's disease|PD]] are:
* Progressive supranuclear palsy (PSP)
* Corticobasal degeneration (CBD)


Some people include dementia with Lewy bodies (DLB) as one of the 'Parkinson-plus' syndromes. Although idiopathic Parkinson's disease patients also have Lewy bodies in their brain tissue, the distribution is denser and more widespread in DLB. Even so, the relationship between Parkinson disease, Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB) might be most accurately conceptualized as a spectrum, with a discrete area of overlap between each of the three disorders. The natural history and role of Lewy bodies is very little understood.
*[[Glucocerebrosidase|Glucocerebrosidase gene]] <ref name="pmid19846850">{{cite journal |vauthors=Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Dürr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG |title=Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease |journal=N. Engl. J. Med. |volume=361 |issue=17 |pages=1651–61 |date=October 2009 |pmid=19846850 |pmc=2856322 |doi=10.1056/NEJMoa0901281 |url=}}</ref>
*[[SNCA]]-associated PD <ref name="pmid17761553">{{cite journal |vauthors=Klein C, Schlossmacher MG |title=Parkinson disease, 10 years after its genetic revolution: multiple clues to a complex disorder |journal=Neurology |volume=69 |issue=22 |pages=2093–104 |date=November 2007 |pmid=17761553 |doi=10.1212/01.wnl.0000271880.27321.a7 |url=}}</ref>
*[[LRRK2]]-associated PD <ref name="pmid11891824">{{cite journal |vauthors=Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F |title=A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1 |journal=Ann. Neurol. |volume=51 |issue=3 |pages=296–301 |date=March 2002 |pmid=11891824 |doi= |url=}}</ref>
*[[Parkin]]-associated PD <ref name="pmid10824074">{{cite journal |vauthors=Lücking CB, Dürr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi BS, Meco G, Denèfle P, Wood NW, Agid Y, Brice A |title=Association between early-onset Parkinson's disease and mutations in the parkin gene |journal=N. Engl. J. Med. |volume=342 |issue=21 |pages=1560–7 |date=May 2000 |pmid=10824074 |doi=10.1056/NEJM200005253422103 |url=}}</ref>
*[[PINK1]]-associated PD <ref name="pmid15087508">{{cite journal |vauthors=Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW |title=Hereditary early-onset Parkinson's disease caused by mutations in PINK1 |journal=Science |volume=304 |issue=5674 |pages=1158–60 |date=May 2004 |pmid=15087508 |doi=10.1126/science.1096284 |url=}}</ref>
*[[DJ-1]]-associated PD <ref name="pmid12446870">{{cite journal |vauthors=Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P |title=Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism |journal=Science |volume=299 |issue=5604 |pages=256–9 |date=January 2003 |pmid=12446870 |doi=10.1126/science.1077209 |url=}}</ref>


Patients often begin with typical Parkinson's disease symptoms which persist for some years; these Parkinson-plus diseases can only be diagnosed when other symptoms become apparent with the passage of time. These Parkinson-plus diseases usually progress more quickly than typical ideopathic Parkinson disease. The usual anti-Parkinson's medications are typically either less effective or not effective at all in controlling symptoms; patients may be exquisitely sensitive to neuroleptic medications like [[haloperidol]]. Additionally, the cholinesterase inhibiting medications have shown preliminary efficacy in treating the cognitive, psychiatric, and behavioral aspects of the disease, so correct differential diagnosis is important.
==Microscopic Pathology==


[[Wilson's disease]] (hereditary copper accumulation) may present with parkinsonistic features; young patients presenting with parkinsonism may be screened for this rare condition. [[Essential tremor]] is often mistaken for Parkinson's disease but usually lacks all features besides tremor.
*The pathologic [[hallmark]] of [[Parkinson's disease|PD]] is the presence of [[Lewy body|lewy bodies]], which are round [[cytoplasmic]] [[eosinophilic]] inclusions. The content of these bodies are mostly [[Alpha-synuclein|alpha synuclein]] and [[ubiquitin]], but we can also find [[Complement|complement proteins]], microflament subunits, and parkin substrate protein.<ref name="pmid14991825">{{cite journal |vauthors=Murakami T, Shoji M, Imai Y, Inoue H, Kawarabayashi T, Matsubara E, Harigaya Y, Sasaki A, Takahashi R, Abe K |title=Pael-R is accumulated in Lewy bodies of Parkinson's disease |journal=Ann. Neurol. |volume=55 |issue=3 |pages=439–42 |date=March 2004 |pmid=14991825 |doi=10.1002/ana.20064 |url=}}</ref>


[[Torsion dystonia]] is another disease related to Parkinson's disease.
*The pathologic manifestations of [[apoptosis]] include condensation of [[chromatin]] and [[cytoplasm]], fragmentation of cell and lysosome-mediated phagocytosis.<ref name="pmid18187492">{{cite journal |vauthors=Pan T, Kondo S, Le W, Jankovic J |title=The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson's disease |journal=Brain |volume=131 |issue=Pt 8 |pages=1969–78 |date=August 2008 |pmid=18187492 |doi=10.1093/brain/awm318 |url=}}</ref> Neuronal [[apoptosis]] occurs in normal individuals (0.5 percent of [[substantia nigra]] [[neurons]]) but in [[Parkinson's disease|PD]] patients this can be as high as 2 percent.<ref name="pmid10809400">{{cite journal |vauthors=Jellinger KA |title=Cell death mechanisms in Parkinson's disease |journal=J Neural Transm (Vienna) |volume=107 |issue=1 |pages=1–29 |date=2000 |pmid=10809400 |doi=10.1007/s007020050001 |url=}}</ref><ref name="pmid12666099">{{cite journal |vauthors=Tatton WG, Chalmers-Redman R, Brown D, Tatton N |title=Apoptosis in Parkinson's disease: signals for neuronal degradation |journal=Ann. Neurol. |volume=53 Suppl 3 |issue= |pages=S61–70; discussion S70–2 |date=2003 |pmid=12666099 |doi=10.1002/ana.10489 |url=}}</ref>.


[[File:Histological_sample_of_Substantia_nigra_in_Parkinson's_disease.jpg|500px|none|thumb|https://librepathology.org/wiki/File:Histological_sample_of_Substantia_nigra_in_Parkinson%27s_disease.jpg]]
[[File:Lewy_bodies_(alpha_synuclein_inclusions).jpg|500px|none|thumb|https://librepathology.org/wiki/File:Lewy_bodies_(alpha_synuclein_inclusions).jpg]]
[[File:Lewy Body alphaSynuclein.jpg|500px|none|thumb|https://librepathology.org/wiki/File:Lewy_Body_alphaSynuclein.jpg]]
[[File:628px-Journal.pone.0008247.g001.png|500px|none|thumb|https://librepathology.org/wiki/File:Journal.pone.0008247.g001.png]]
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

Latest revision as of 19:09, 17 October 2021


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

Overview

The underlying pathophysiology of Parkinson disease is dopamine depletion. Reduced number of dopaminergic neurons lead to increased inhibition of thalamus and as a result, decrease excitation of brain cortex, causing bradykinesia. pathologic hallmark of PD is lewy bodies which are round cytoplasmic eosinophilic inclusions. This disease can have so many triggers ( Protein misfolding, Defective proteolysis, Mitochondrial dysfunction, Oxidative stress, Iron metabolism and Immunologic and inflammatory mechanisms) but the main etiology of neuronal degeneration is either apoptosis or necrosis.

Pathophysiology

Physiology

Phatogenesis

Protein misfolding

Defective proteolysis

  • There are three pathways which control the protein homeostasis in cells: Molecular chaperons, the ubiquitin-proteasome system and autophagy-lysosomal pathway.
  • Alpha synuclein processing is done by all of this three mechanisms and defect in any of them can cause aggregation of this protein and neuronal death.[18][19][20]

Mitochondrial dysfunction

  • The drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an analog of mepridine is found to be associated with PD.
  • The oxidation of this drug produces 1-methyl-4-phenylpyridium which inhibits complex one of mitochondria and result in cell damage.
  • Studies showed that the activity of this complex is decreased in PD patients.[21][22][23]

Oxidative stress

Iron metabolism

Immunologic and inflammatory mechanisms

Genetics

  • There are some evidence showing that there is an association between PD and genetic.
  • This role is higher when Parkinson disease occurs in the individual younger than 50 years old.[33]
  • These studies also demonstrate that if a person has a first degree with PD, the risk of developing PD is 2 to 3 times higher than normal population. Conversely, in 25 to 50 % of PD patients we can find at least one first degree having PD.[34]

Some of specific genes involving in PD are:

Microscopic Pathology

https://librepathology.org/wiki/File:Histological_sample_of_Substantia_nigra_in_Parkinson%27s_disease.jpg
https://librepathology.org/wiki/File:Lewy_bodies_(alpha_synuclein_inclusions).jpg
https://librepathology.org/wiki/File:Lewy_Body_alphaSynuclein.jpg
https://librepathology.org/wiki/File:Journal.pone.0008247.g001.png

References

  1. ↑ Gerfen CR (October 2000). "Molecular effects of dopamine on striatal-projection pathways". Trends Neurosci. 23 (10 Suppl): S64–70. PMID 11052222.
  2. ↑ Bamford NS, Robinson S, Palmiter RD, Joyce JA, Moore C, Meshul CK (October 2004). "Dopamine modulates release from corticostriatal terminals". J. Neurosci. 24 (43): 9541–52. doi:10.1523/JNEUROSCI.2891-04.2004. PMID 15509741.
  3. ↑ Gatev P, Darbin O, Wichmann T (October 2006). "Oscillations in the basal ganglia under normal conditions and in movement disorders". Mov. Disord. 21 (10): 1566–77. doi:10.1002/mds.21033. PMID 16830313.
  4. ↑ Calabresi P, Centonze D, Bernardi G (October 2000). "Electrophysiology of dopamine in normal and denervated striatal neurons". Trends Neurosci. 23 (10 Suppl): S57–63. PMID 11052221.
  5. ↑ Moore H, Grace AA (December 2002). "A role for electrotonic coupling in the striatum in the expression of dopamine receptor-mediated stereotypies". Neuropsychopharmacology. 27 (6): 980–92. doi:10.1016/S0893-133X(02)00383-4. PMID 12464455.
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