A defining characteristic of Parkinson's disease (PD) is the prominent degeneration and loss of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNpc) region of the brain; however, it is not clear why this population of DA neurons is preferentially targeted in PD.
In this issue of the Journal of Clinical Investigation, Huaibin Cai and colleagues at the National Institute on Aging identified a subpopulation of SNpc DA neurons lacking aldehyde dehydrogenase 1 (ALDH1A1) that are especially prone to degeneration and accumulation of cytotoxic levels of α-synuclein in a murine model of PD.
Evaluation of PD patient and healthy brains revealed a reduction ALDH1A1 expression and reduced numbers of ALDH1A1-expressing DA neurons in the SNpc of PD patients. In PD mice, deletion of Aldh1a1 exacerbated both the loss of DA neurons and α-synuclein aggregation. Expression of ALDH1A1 in cultured DA neurons from PD mice enhanced cell survival, preventing caspase-mediated cell death. Together, the results from this study suggest that reduced ALDA1A1 expression in PD DA neurons makes this population vulnerable to α-synuclein-mediated degeneration.