Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation.

ABSTRACT: Subpopulations of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNpc) display a differential vulnerability to loss in Parkinson's disease (PD); however, it is not clear why these subsets are preferentially selected in PD-associated neurodegeneration. In rodent SNpc, DA neurons can be divided into two subpopulations based on the expression of aldehyde dehydrogenase 1 (ALDH1A1). Here, we have shown that, in ?-synuclein transgenic mice, a murine model of PD-related disease, DA neurodegeneration occurs mainly in a dorsomedial ALDH1A1-negative subpopulation that is also prone to cytotoxic aggregation of ?-synuclein. Notably, the topographic ALDH1A1 pattern observed in ?-synuclein transgenic mice was conserved in human SNpc. Postmortem evaluation of brains of patients with PD revealed a severe reduction of ALDH1A1 expression and neurodegeneration in the ventral ALDH1A1-positive DA subpopulations. ALDH1A1 expression was also suppressed in ?-synuclein transgenic mice. Deletion of Aldh1a1 exacerbated ?-synuclein-mediated DA neurodegeneration and ?-synuclein aggregation, whereas Aldh1a1-null and control DA neurons were comparably susceptible to 1-methyl-4-phenylpyridinium-, glutamate-, or camptothecin-induced cell death. ALDH1A1 overexpression appeared to preferentially protect against ?-synuclein-mediated DA neurodegeneration but did not rescue ?-synuclein-induced loss of cortical neurons. Together, our findings suggest that ALDH1A1 protects subpopulations of SNpc DA neurons by preventing the accumulation of dopamine aldehyde intermediates and formation of cytotoxic ?-synuclein oligomers.

SUBMITTER: Liu G 

PROVIDER: S-EPMC4071380 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature