Alpha-Synuclein Misfolding and Aggregation in Parkinson's Disease

Parkinson’s disease (PD) is a fatal neurodegenerative disorder that affects 1.5 millions Americans and 1 in 100 individuals over the age of 60. It results from neuronal atrophy localized within the substantia nigra pars compacta. Upon autopsy, PD patients have large intraneuronal fibrils, Lewy Bodies, composed of a-synuclein. Familial forms of PD result from the A30P and A53T mutations within a-synuclein. Wild-type (WT), A30P, and A53T-a-synuclein aggregate from monomers into protofibrils before forming fibrils. Previously, fibrils were thought to be the PD causative agent however, recent evidence suggests that the protofibril may be the true toxic conformation of a-synuclein. In 2004, Zarranz et al. discovered a novel mutation, a-synuclein-E46K, in a Spanish family. Little is known about this mutation, except that it increases the rate and quantity of fibril formation as well as the lipid binding affinity of á-synuclein. The fibril formation pathway for E46K is unknown, though it likely includes a protofibrillar intermediate. Future research is needed to characterize E46K and compare it to the other familial mutants. Treatment approaches aimed at reducing the concentration of protofibrils could be accomplished through accelerated fibril formation, decreased a-synuclein expression, increased a-synuclein degradation, or reduction of intracellular dopamine which binds and stabilizes protofibril.