Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 124, Issue 7, Pages 3032-3046Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI72176
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Funding
- National Institute on Aging [AG000959-07, AG000945-03]
- NIH funding of the Johns Hopkins University Alzheimer's Disease Research Center [P50AG05146]
- Morris K. Udall Centers of Excellence in Parkinson's Disease Research
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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 alpha-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 alpha-synuclein. Notably, the topographic ALDH1A1 pattern observed in alpha-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 alpha-synuclein transgenic mice. Deletion of Aldh1a1 exacerbated alpha-synuclein-mediated DA neurodegeneration and alpha-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 alpha-synuclein-mediated DA neurodegeneration but did not rescue alpha-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 alpha-synuclein oligomers.
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