Parkinson’s Disease

Parkinson’s disease (PD) has the second-highest prevalence as a neurological disorder after Alzheimer’s disease 1. It is also described as ‘’progressive movement disorder’’ 2. It was first identified as “shaking palsy” by James Parkinson in 1817 3 4. Prevalence of PD is nearly 4% of the individuals older than age 85 1. Global prevalence of PD is anticipated to double by 2040 5. Tremor, rigidity, bradykinesia (slow movements), stiffness in the muscle, and unstable posture are among the symptoms of PD 6.

When a human is getting older, her/his neurons die out without replacement  7. Death of the neurons results in the emergence of PD 8. The neurons generate dopamine which controls the movement of the body 9. The level of dopamine generated in the brain declines when neurons die 9. Neuropathological research revealed the subsistence of α-synuclein-involving Lewy bodies which are intraneuronal inclusions comprised of α-synuclein/αS protein aggregates in the substantia nigra of the brain 10 11. Attenuated facilitation of voluntary movements is caused by deprivation of dopaminergic neurons in the pars compacta of the substantia nigra 10. Accumulation of αS spreads in the brain during the progression of PD 12.

Figure1: αS/lipid homeostasis and dyshomeostasis: disequilibrium leads to αS to form membranous non-fibrillar or membrane-mediated fibrillar aggregates because of unnatural lipid interactions.

The familial or sporadic form of degenerative parkinsonian diseases can be encountered, both forms possess deprivation of the dopaminergic neurons in the substantia nigra 11.  Cell death causes impairment of the integrity of nuclear membrane and liberation of nuclear factors 13. αS protein (14 kDa) whose expression is high in the brain is strongly involved in Parkinson’s disease 14 15. αS-rich cytoplasmic inclusions (also called Lewy bodies (LBs)) and Lewy neurites are the indicator lesions of synucleinopathies. Excessiveness of interactions of αS–membrane may set off aggregation of proteinaceous αS by stimulating its primary nucleation 16. However, αS may also create its toxicity before or independent of its self-aggregation, e.g., via excessive membrane interactions that may be promoted by certain lipids and fatty acids 17 14. Association of cell death with disruption of the integrity of nuclear membrane and liberation of pro-aggregate nuclear factors which can set off αS aggregation 13. Once the aggregation starts, it may then spread to other cells in direct or indirect ways 18αS is known as a natively unfolded protein that is enriched in presynaptic terminals where it possesses a role in synaptic vesicle liberation, so the existence of αS in cytoplasmic inclusions reflects abnormal cytologic localization, 19. Anomalous αS in PD possesses unusual protein conformation that leads to form aggregations, pathologic post-translational variations, phosphorylation, oxidative damage, truncation can be encountered in αS aberrantly present in PD 20.

Figure2: αS-lipid interplay

90 to 95% of PD are sporadic with uncertain sources. Autophagy provides the disposal of long-lived proteins and non-functional organelles in cells of eukaryotes to hamper further toxicity and cell death. Impaired autophagic-lysosomal degradation results in aggregation of αS and protein tau 21. It is known that αS and tau affect mitochondrial, autophagic, and lysosomal functions 21 22. Metabolically active dopaminergic neurons require high mitochondrial energy requests, so they are very sensitive to inadequate clearance of damaged mitochondria 23. The raised level of ROS (reactive oxygen species) results from an accumulation of the defective mitochondria 24.

1 to 2% of the population, especially older age ones, are affected by PD each year 10. Generally, it affects upon men more often than women 10. The major signs of PD are bradykinesia which means slowness of movement [1], rigidity which is stiff or inflexible muscles [2], and rest-tremor 10. Frequently, the new diagnostic criteria include supportive criteria, absolute exclusion criteria, and red flags. At least 2 supportive criteria need to be encountered to diagnose ‘‘clinically established PD’’ 10.  Motor and non-motor features of the disease which have an impact on are involved in dopaminergic therapy, dyskinesia that is involuntary, unguessable, squirming movements of the face, arms, legs, or trunk are among the supportive criteria of PD 10. Absolute exclusion criteria involve cerebellar abnormalities, frontotemporal cognitive variations, etc. 10.

The most potent drug for PD is Levodopa. It acts as an immediate precursor of dopamine and ables it to cross the Blood-Brain Barrier 25. Production of more dopamine and alleviation of symptoms of PD are achieved by the drug. Carbidopa is used together with Levodopa because it provides prevention of the metabolism of Levodopa in the periphery, rising central nervous system (CNS) bioavailability, and alleviating peripheral side effects 25. Dopamine agonists are utilized to stimulate dopaminergic receptors in the CNS. However the agonists can lessen the symptoms of PD and possess a longer half-life, they are less potent in comparison to Levodopa 25.

REFERENCES

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  9. Oh SL, Hagiwara Y, Raghavendra U, et al. A deep learning approach for Parkinson’s disease diagnosis from EEG signals. Neural Comput Appl. Published online 2020. doi:10.1007/s00521-018-3689-5
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  14. Fanning S, Selkoe D, Dettmer U. Parkinson’s disease: proteinopathy or lipidopathy? npj Park Dis. Published online 2020. doi:10.1038/s41531-019-0103-7
  15. Sastry PS. Lipids of nervous tissue: Composition and metabolism. Prog Lipid Res. Published online 1985. doi:10.1016/0163-7827(85)90011-6
  16. Galvagnion C, Buell AK, Meisl G, et al. Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation. Nat Chem Biol. Published online 2015. doi:10.1038/nchembio.1750
  17. Dettmer U, Ramalingam N, von Saucken VE, et al. Loss of native α-synuclein multimerization by strategically mutating its amphipathic helix causes abnormal vesicle interactions in neuronal cells. Hum Mol Genet. Published online 2017. doi:10.1093/HMG/DDX227
  18. Jiang P, Gan M, Yen SH, McLean PJ, Dickson DW. Histones facilitate α-synuclein aggregation during neuronal apoptosis. Acta Neuropathol. Published online 2017. doi:10.1007/s00401-016-1660-z
  19. Burré J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Südhof TC. α-Synuclein promotes SNARE-complex assembly in vivo and in vitro. Science (80- ). Published online 2010. doi:10.1126/science.1195227
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  21. Wang Y, Martinez-Vicente M, Krüger U, et al. Tau fragmentation, aggregation and clearance: The dual role of lysosomal processing. Hum Mol Genet. Published online 2009. doi:10.1093/hmg/ddp367
  22. Caballero B, Wang Y, Diaz A, et al. Interplay of pathogenic forms of human tau with different autophagic pathways. Aging Cell. Published online 2018. doi:10.1111/acel.12692
  23. Bolam JP, Pissadaki EK. Living on the edge with too many mouths to feed: Why dopamine neurons die. Mov Disord. Published online 2012. doi:10.1002/mds.25135
  24. Hou X, Watzlawik JO, Fiesel FC, Springer W. Autophagy in Parkinson’s Disease. J Mol Biol. Published online 2020. doi:10.1016/j.jmb.2020.01.037
  25. Hayes MT. Parkinson’s Disease and Parkinsonism. Am J Med. Published online 2019. doi:10.1016/j.amjmed.2019.03.001

Figure Referance:

  1.  Fanning S, Selkoe D, Dettmer U. Parkinson’s disease: proteinopathy or lipidopathy? npj Park Dis. Published online 2020. doi:10.1038/s41531-019-0103-7
  2. Fanning S, Selkoe D, Dettmer U. Parkinson’s disease: proteinopathy or lipidopathy? npj Park Dis. Published online 2020. doi:10.1038/s41531-019-0103-

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