“Janus-Faced” alpha-Synuclein: Role in Parkinson’s Disease

Parkinson’s disease (PD) is a pathological condition characterized by the aggregation
and the resultant presence of intraneuronal inclusions termed Lewy bodies (LBs)
and Lewy neurites which are mainly composed of fibrillar a-synuclein (a-syn) protein.
Pathogenic aggregation of a-syn is identified as the major cause of LBs deposition.
Several mutations in a-syn showing varied aggregation kinetics in comparison to the
wild type (WT) a-syn are reported in PD (A30P, E46K, H 50Q, G51D, A53E, and
A53T). Also, the cell-to-cell spread of pathological a-syn plays a significant role in
PD development. Interestingly, it has also been suggested that the pathology of PD
may begin in the gastrointestinal tract and spread via the vagus nerve (VN) to brain
proposing the gut–brain axis of a-syn pathology in PD. Despite multiple efforts, the
behavior and functions of this protein in normal and pathological states (specifically
in PD) is far from understood. Furthermore, the etiological factors responsible for
triggering aggregation of this protein remain elusive. This review is an attempt to collate
and present latest information on a-syn in relation to its structure, biochemistry and
biophysics of aggregation in PD. Current advances in therapeutic efforts toward clearing
the pathogenic a-syn via autophagy/lysosomal flux are also reviewed and reported