Alexandra Browne

Background: Parkinson disease (PD) is one of multiple neurodegenerative diseases that is caused by the pathogenic accumulation of misfolded alpha-synuclein proteins, a disease process collectively referred to as synucleinopathies.^1,2,3 PD impacts more than 6 million people today, with the incident rate expected to double by the year 2040.² One prevailing theory of PD onset is inflammation of the enteric nervous system causes the misfolding and aggregation of alpha-synuclein proteins eventually spreading to the brain.⁴ Although the exact pathogenesis is still unclear; extensive research into the protein molecular structure has revealed the capacity of misfolded protein aggregates to proliferate and propagate among healthy neurons in an almost prion-like fashion.^1,2,3,4 Existing therapies of synucleinopathies has yet to exploit these most recent findings.

Objective: This literature review explored how alpha-synuclein proteins become pathogenic and propagate within healthy neuronal cells.

Search Methods: An online search in the PubMed database was conducted, identifying literature from 2020-2023 using the following keywords:” alpha-synuclein”, “Parkinson disease”, “electrostatic interactions”, “protein folding”, and “Lewy bodies”

Results: Alpha-synuclein protein comprises 3 environmentally distinct domains: the N-terminal with an amphipathic nature, the second domain a hydrophobic non-amyloid component (NAC), and the third domain with a charged C-terminus.^1,2 Cryo-electron microscopy (cryo-EM) was used to compare the 3D structure of PD and MSA fibrils, synucleinopathies that display distinct charged surfaces and inter-protofilament electrostatic interactions.⁵ The findings indicated that quaternary morphologic arrangements create distinct pathogenesis among synucleinopathies.⁵ Introduction of enteric neurons in mice sampled from a PD patient exhibited statistically significant alpha synuclein pathogenicity in microglia.⁴   Whereas MSA fibrils demonstrate a higher potential for neurotoxicity and pathogenicity in oligodendroglia.⁵ Furthermore, cryo-EM was also able to delineated the capacity of post-translational modifications (PTMs) to induce structural and functional changes in the alpha-synuclein protein.^1,6 The most commonly observed hallmark of Lewy body formations being phosphorylated PTMs.^6,7 Moreover, phosphorylation altered the alpha-synuclein quaternary structure resulting in the shielding of protein cleavage sites from proteases.^6,7 In contrast, alpha-synuclein protein monomers in the absence of pathology adopt a configuration that shields the charged C-terminal preventing Lewy body formation.^6,7 Flavonoid epigallocatechin gallate (EGCG), found in green tea, demonstrates the capacity to disassemble preformed amyloid fibrils. However, EGCG is a very polar molecule incapable of penetrating the blood-brain barrier (BBB).⁸ Using EGCG as a pharmacological mechanistic template, peptides CNS-11 and its analog CNS-11g were discovered, with the capacity to cross the BBB and disassemble alpha-synuclein aggregates.⁸ The theorized mechanism was, CNS-11 peptide is attracted to the unstable charges at N-terminal, and in collaboration with existent cell machinery (heat shock proteins), is capable of reverting misfolded fibrillar proteins.⁸

Conclusions: These studies together demonstrate that disruption of electrostatic interactions may delay disease progression, or symptom manifestation associated with pathologic misfolded alpha-synuclein proteins.

Works Cited:

1. Ma J, Gao J, Wang J, Xie A. Prion-Like Mechanisms in Parkinson’s Disease. Front Neurosci. 2019;13:552. 2019;18. doi:10.3389/fnins.2019.00552
2. Öksüz N, Öztürk Ş, Doğu O. Future Prospects in Parkinson’s Disease Diagnosis and Treatment. Archives of neuropsychiatry. 2022;59(Suppl 1):S36-S41. 2022. doi:10.29399/npa.28169
3. Mehra S, Sahay S, Maji SK. α-Synuclein misfolding and aggregation: Implications in Parkinson’s disease pathogenesis. Biochim Biophys Acta Proteins Proteom. 2019;1867(10):890-908. doi:10.1016/j.bbapap.2019.03.001
4. Yang Z, Wang Y, Wei M, et al. Intrastriatal injection of Parkinson’s disease intestine and vagus lysates initiates α-synucleinopathy in rat brain. Cell Death Dis. 2023;14(1):4. doi:10.1038/s41419-022-05531-z
5. Frieg B, Geraets JA, Strohäker T, et al. Quaternary structure of patient-homogenate amplified α-synuclein fibrils modulates seeding of endogenous α-synuclein. Commun Biol. 2022;5(1):1040. doi:10.1038/s42003-022-03948-y
6. Zhao K, Lim YJ, Liu Z, et al. Parkinson’s disease-related phosphorylation at Tyr39 rearranges α-synuclein amyloid fibril structure revealed by cryo-EM. Proc Natl Acad Sci U S A. 2020;117(33):20305-20315. doi:10.1073/pnas.1922741117
7. Zhang S, Liu YQ, Jia C, et al. Mechanistic basis for receptor-mediated pathological αsynuclein fibril cell-to-cell transmission in Parkinson’s disease. Proc Natl Acad Sci U S A. 2021;118(26):e2011196118. doi:10.1073/pnas.2011196118
8. Murray KA, Hu CJ, Pan H, et al. Small molecules disaggregate alpha-synuclein and prevent seeding from patient brain-derived fibrils. Proc Natl Acad Sci U S A. 2023;120(7):e2217835120. doi:10.1073/pnas.2217835120