Alpha synuclein aggregation: mechanism and role in PD

As a-syn is the most abundant protein composing the proteinaceous aggregates that define PD on a pathologic level, intense efforts revolve around understanding a-syn
accumulation and aggregation. a-Syn may assume oligomeric species through unknown mechanisms, and higher-order a-syn structures usually correlate with a-syn–dependent toxicity in cells (Fig). The specific conformational entities responsible
for protection, toxicity, and / or aggregation remain elusive. Factors known to modify a-syn aggregation and/or oligomerization include alterations of the primary amino acid sequence (e.g., PD-associated mutations); c-terminal truncations,
interactions with metal ions; interactions with Ab peptide; interactions with chaperone proteins such as Hsp70; interactions with apolipoprotein E, as well as
neurotoxins, pesticides, and herbicides; organic solvents; tyrosine nitration; phosphorylation; methionine oxidation; monoubiquitination; interaction with
polyanions and polycations, oxidative dimmers, and oligomers; histones; transglutaminase;and other protein–protein interactions.
As in other neurodegenerative disorders and diseases associated with protein aggregation, the role of organized inclusion bodies localized to disease-associated regions in PD affected tissue remains hotly debated. On the one hand, the
inclusion-body organelles may serve to sequester molecules that, for whatever reason, can no longer route through normal metabolism that would otherwise cause cellular dysfunction.
Experimental evidence supports this notion, in which the lack of a-syn–inclusion formation associates with toxicity. In contrast, the overt formation of inclusions may represent the toxic insult itself composed of molecules that were otherwise
nontoxic until association with the inclusion. In the first case, promoting inclusion bodies should facilitate neuroprotection. In the second case, inhibiting inclusion bodies would promote cell toxicity. Both situations may be true,
depending on the particular component of the inclusion body in question; for example, sequestration of toxic a-syn species into inclusion bodies may represent cytoprotection, with the cost of sequestering and inactivating other molecules necessary for normal function.
Therapeutically oriented efforts should focus on farther upstream events as opposed to modifying preexisting inclusion bodies, although this may be a moot point because model systems that demonstrate inclusions with morphologic similarity to Lewy bodies have yet to be developed. One major obstacle to understanding Lewy bodies is the failure to recapitulate the basic morphologic characteristics of Lewy bodies
in the context of relevant model systems. Although several model systems describe a-syn– and ubiquitin-positive aggregations in some fraction of cells, none can be
considered similar to the highly ordered structures found in PD tissue.
As a potential therapeutic target, the accumulation of a-syn into insoluble protein inclusions seems an important event in pathogenesis. A strong case can be made for therapeutically promoting inclusion formation in disease to protect cells from
more-soluble toxic species, as well as therapeutic approaches to dissolve inclusions to relieve the cells of a deleterious organelle that disrupts normal function. The dichotomy may not be resolved in the near future and hinders a-syn– antiaggregation strategies as a viable therapeutic approach.