Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation

作者：Liu, Guoxiang; Yu, Jia; Ding, Jinhui; Xie, Chengsong; Sun, Lixin; Rudenko, Iakov; Zheng, Wang; Sastry, Namratha; Luo, Jing; Rudow, Gay; Troncoso, Juan C.; Cai, Huaibin^*

来源：Journal of Clinical Investigation, 2014, 124(7): 3032-3046.

DOI：10.1172/JCI72176

• MUTANT ALPHA-SYNUCLEIN
• PARKINSONS-DISEASE
• SUBSTANTIA-NIGRA
• MICE
• VULNERABILITY
• METABOLITE
• BRAIN
• 3,4-DIHYDROXYPHENYLACETALDEHYDE
• NEUROTOXICITY
• PATHOGENESIS

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.

• 出版日期2014-7
• 单位NIH; 北京师范大学