Pathological roles of α-synuclein in neurological disorders

Substantial genetic, neuropathological, and biochemical evidence implicates the presynaptic neuronal protein alpha-synuclein in Parkinson's disease and related Lewy body disorders. How dysregulation of alpha-synuclein leads to neurodegeneration is, however, unclear. Soluble oligomeric, but not fully fibrillar, alpha-synuclein is thought to be toxic. The major neuronal target of aberrant alpha-synuclein might be the synapse. The effects of aberrant alpha-synuclein might include alteration of calcium homoeostasis or mitochondrial fragmentation and, in turn, mitochondrial dysfunction, which could link alpha-synuclein dysfunction to recessive and toxin-induced parkinsonism. alpha-Synuclein also seems to be linked to other genetic forms of Parkinson's disease, such as those linked to mutations in GBA or LRRK2, possibly through common effects on autophagy and lysosomal function. Finally, alpha-synuclein is physiologically secreted, and this extracellular form could lead to the spread of pathological accumulations and disease progression. Consequently, factors that regulate the levels, post-translational modifications, specific aberrant cellular effects, or secretion of alpha-synuclein might be targets for therapy.