Therapeutic targets for PD (Contd..)

As discussed before, targeting alpha-synuclein for prevention of neurodegeneration and vying for neurorestoration would be a good therapeutic target. alpha-synulein aggregation has been one of the most widely cited cause leading to Lew Bodies and finally to Dopamineric cell death. Now: what causes the alpha-synuclein molecule to aggregate ? What is the mechanism of the aggregation ?
Being the most abundant protein comprising the proteinacious aggregates that define PD on pathologic level, intense efforts revolve around understanding alpha-synuclein accumulation and aggregation. alpha-synuclein may assume oligomeric species through unknown mechanisms, and higher-order alpha-synuclein structures usually correlate with toxicity in cells. What specific conformational entities are directly responsible for protection, toxicity and/or aggregation remain elusive. Factors known to modify alpha-synuclein aggregation and/or oligomerization include mutations in the primary amino acid sequence (e.g., PD-associated mutations: A30P, E46K, A53T), C-terminal truncations, interactions with metal ions, interactions with Aβ peptide, interactions with chaperone proteins such as Hsp40, Hsp70, interactions with apolipoprotein E, as well as neurotoxins, pesticides and herbicides, organic solvents, tyrosine nitration, phosphorylation, methionine oxidation, monoubiquitination, interaction with polyanions & polycations, oxidative dimers, histones, transglutaminase, and other protein-protein interactions, as well as other processes including mitochondrial dysfunction, oxidative stress, neuroinflammation, l-DOPA treatment and DA metabolism etc.

As a potential therapeutic target of action, the accumulation of alpha-synuclein into insoluble protein inclusions seems to be an important event in pathogenesis, yet a strong case can be made for therapeutically promoting inclusion formation in disease to protect cells from more soluble toxic species, as well as therapeutically dissolving inclusions to relieve the cells of a deleterious organelle that disrupts normal function. This dichotomy hinders alpha-synuclein as a viable target for therapeutics.