Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation

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

Research output: Contribution to journalArticlepeer-review

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 α-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 α-synuclein. Notably, the topographic ALDH1A1 pattern observed in α-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 α-synuclein transgenic mice. Deletion of Aldh1a1 exacerbated α-synuclein-mediated DA neurodegeneration and α-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 α-synuclein-mediated DA neurodegeneration but did not rescue α-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 α-synuclein oligomers.

Original languageEnglish (US)
Pages (from-to)3032-3046
Number of pages15
JournalJournal of Clinical Investigation
Volume124
Issue number7
DOIs
StatePublished - Jul 1 2014

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint

Dive into the research topics of 'Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation'. Together they form a unique fingerprint.

Cite this