Parkinson's disease pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
The underlying pathophysiology of Parkinson disease is dopamine depletion.The substantia nigra (SN), striatum (caudate and putamen), globus pallidus (GP), 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 mediated by glutamate. The major dopaminergic neurons are in substantia nigra and are responsible for dopaminergic input of striatum. The striatal output is inhibitory (GABA) despite the excitatory (glutamate) output of STN to the globus pallidus (medial and lateral). There are 5 dopamine receptors (D1_D5) which are in basal ganglia and limbic system. D1 and D2 are mostly found in the dorsal striatum (motor) and are activated through dopaminergic pathway from SNc, as a result, they are very important in the pathophysiology of Parkinson disease. D3 and D4 are located mostly in mesolimbic or emotional part of the brain and D5 in hippocampus/hypothalamus area.[1] In the course of the disease dopamine depletion of nigrostriatal pathway will lead to denervation hypersensitivity and increasing number of D2 receptors in dorsal putamen.[2] There are two pathways in this system: Direct and indirect pathway. In the indirect pathway starts with inhibition of striatum via D2 receptor which in turn inhibits neurons of lateral GP by GABA which inhibits the inhibition of STN by lateral GP. STN provides excitatory action on GP internal and SNr via glutamate. GPi inhibit thalamus by GABA but cortex input from thalamus is excitatory. Direct pathway starts with excitation of striatum by stimulation of D1 receptors, then striatum inhibits GP internal and SNr by GABA directly. Reduced number of dopaminergic neurons lead to increased inhibition of thalamus and as a result, decrease excitation of brain cortex, causing bradykinesia.[3] Our brain has some compensatory mechanism fighting dopamine depletion. It can increase the synthesis of dopamine, gap junctions and the number of D2 receptors.[4][5] It can also reduce the uptake of dopamine from synaptic space.[6] The main pathology seen in 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 SN in a normal individual is about 550,000, but in patient with PD in can decrease as much as 66%.[7] In the normal aging process, neuronal loss occurs in the dorsal tier of 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 SN.[8][9] The other sites of the brain which are influenced by PD are internal segment of the globus pallidus, center median parafascicular complex, pedunculopontine tegmental nucleus, glutamatergic caudal intralaminar thalamic nuclei and hippocampus.[10][11] pathologic hallmark of PD is lewy bodies which are round cytoplasmic eosinophilic inclusions. The content of this bodies are mostly alpha synuclein and ubiquitin, but also we can find complement proteins, microflament subunits and parkin substrate protein.[12] PD may have so many triggers but the main etiology of neuronal degeneration is either apoptosis or necrosis.[13][14][15]
The pathologic manifestations of apoptosis include condensation of chromatin and cytoplasm, fragmentation of cell and lysosome-mediated phagocytosis.[16] Neuronal apoptosis occurs in normal individuals (0.5 percent of substantia nigra neurons) but in PD patients this can be as high as 2 percent.[17][18]
Protein misfolding
One of the main underlying cause of 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.[19][20] This mutations lead to unfold alpha-synuclein and aggregation of insoluble protein and neuronal damage. Lewy bodies which are characteristic of PD are mostly build from alpha-synuclein protein.[21]
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.[22][23][24]
Mitochondrial dysfunction
References
- ↑ Gerfen CR (October 2000). "Molecular effects of dopamine on striatal-projection pathways". Trends Neurosci. 23 (10 Suppl): S64–70. PMID 11052222.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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 (December 2005). "PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation". Brain. 128 (Pt 12): 2777–85. doi:10.1093/brain/awh607. PMID 16081470.
- ↑ Pakkenberg B, Møller A, Gundersen HJ, Mouritzen Dam A, Pakkenberg H (January 1991). "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". J. Neurol. Neurosurg. Psychiatry. 54 (1): 30–3. PMC 1014294. PMID 2010756.
- ↑ Porritt M, Stanic D, Finkelstein D, Batchelor P, Lockhart S, Hughes A, Kalnins R, Howells D (July 2005). "Dopaminergic innervation of the human striatum in Parkinson's disease". Mov. Disord. 20 (7): 810–8. doi:10.1002/mds.20399. PMID 15726582.
- ↑ Fearnley JM, Lees AJ (October 1991). "Ageing and Parkinson's disease: substantia nigra regional selectivity". Brain. 114 ( Pt 5): 2283–301. PMID 1933245.
- ↑ Henderson JM, Carpenter K, Cartwright H, Halliday GM (March 2000). "Degeneration of the centré median-parafascicular complex in Parkinson's disease". Ann. Neurol. 47 (3): 345–52. PMID 10716254.
- ↑ Camicioli R, Moore MM, Kinney A, Corbridge E, Glassberg K, Kaye JA (July 2003). "Parkinson's disease is associated with hippocampal atrophy". Mov. Disord. 18 (7): 784–90. doi:10.1002/mds.10444. PMID 12815657.
- ↑ Murakami T, Shoji M, Imai Y, Inoue H, Kawarabayashi T, Matsubara E, Harigaya Y, Sasaki A, Takahashi R, Abe K (March 2004). "Pael-R is accumulated in Lewy bodies of Parkinson's disease". Ann. Neurol. 55 (3): 439–42. doi:10.1002/ana.20064. PMID 14991825.
- ↑ Savitt JM, Dawson VL, Dawson TM (July 2006). "Diagnosis and treatment of Parkinson disease: molecules to medicine". J. Clin. Invest. 116 (7): 1744–54. doi:10.1172/JCI29178. PMC 1483178. PMID 16823471.
- ↑ Lang AE (March 2007). "The progression of Parkinson disease: a hypothesis". Neurology. 68 (12): 948–52. doi:10.1212/01.wnl.0000257110.91041.5d. PMID 17372132.
- ↑ Atkin G, Paulson H (2014). "Ubiquitin pathways in neurodegenerative disease". Front Mol Neurosci. 7: 63. doi:10.3389/fnmol.2014.00063. PMC 4085722. PMID 25071440.
- ↑ Pan T, Kondo S, Le W, Jankovic J (August 2008). "The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson's disease". Brain. 131 (Pt 8): 1969–78. doi:10.1093/brain/awm318. PMID 18187492.
- ↑ Jellinger KA (2000). "Cell death mechanisms in Parkinson's disease". J Neural Transm (Vienna). 107 (1): 1–29. doi:10.1007/s007020050001. PMID 10809400.
- ↑ Tatton WG, Chalmers-Redman R, Brown D, Tatton N (2003). "Apoptosis in Parkinson's disease: signals for neuronal degradation". Ann. Neurol. 53 Suppl 3: S61–70, discussion S70–2. doi:10.1002/ana.10489. PMID 12666099.
- ↑ Maries E, Dass B, Collier TJ, Kordower JH, Steece-Collier K (September 2003). "The role of alpha-synuclein in Parkinson's disease: insights from animal models". Nat. Rev. Neurosci. 4 (9): 727–38. doi:10.1038/nrn1199. PMID 12951565.
- ↑ Calo L, Wegrzynowicz M, Santivañez-Perez J, Grazia Spillantini M (February 2016). "Synaptic failure and α-synuclein". Mov. Disord. 31 (2): 169–77. doi:10.1002/mds.26479. PMID 26790375.
- ↑ Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (August 1997). "Alpha-synuclein in Lewy bodies". Nature. 388 (6645): 839–40. doi:10.1038/42166. PMID 9278044.
- ↑ Lim KL, Zhang CW (2013). "Molecular events underlying Parkinson's disease - an interwoven tapestry". Front Neurol. 4: 33. doi:10.3389/fneur.2013.00033. PMC 3619247. PMID 23580245.
- ↑ Dehay B, Martinez-Vicente M, Caldwell GA, Caldwell KA, Yue Z, Cookson MR, Klein C, Vila M, Bezard E (June 2013). "Lysosomal impairment in Parkinson's disease". Mov. Disord. 28 (6): 725–32. doi:10.1002/mds.25462. PMC 5131721. PMID 23580333.
- ↑ 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 (January 2014). "Autophagy and apoptosis dysfunction in neurodegenerative disorders". Prog. Neurobiol. 112: 24–49. doi:10.1016/j.pneurobio.2013.10.004. PMID 24211851.