Could a loss of α‐synuclein function put dopaminergic neurons at risk?

The α‐synuclein gene is implicated in Parkinson's disease, the symptoms of which occur after a marked loss of substantia nigra dopamine neurons. While the function of α‐synuclein is not entirely elucidated, one function appears to be as a normal regulatory protein that can bind to and inhibit tyrosine hydroxylase, the rate‐limiting enzyme in dopamine synthesis. Soluble α‐synuclein levels may be diminished in Parkinson's disease substantia nigra dopamine neurons both by reduced expression and by α‐synuclein aggregation as Lewy bodies and Lewy neurites form. The loss of functional α‐synuclein may then result in dysregulation of tyrosine hydroxylase, dopamine transport and dopamine storage, resulting in excess cytosolic dopamine. Because dopamine and its metabolites are reactive molecules capable of generating highly reactive quinones and reactive oxygen species, a failure to package dopamine into vesicles could cause irreversible damage to cellular macromolecules and contribute to resultant neurotoxicity. This review focuses on how a loss of normal α‐synuclein function may contribute to the dopamine‐related loss of substantia nigra neurons during Parkinson's disease pathogenesis.