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
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
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Research Article Neuroscience

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 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.

Authors

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

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Figure 1

ALDH1A1-negative nigrostriatal DA neurons in the dorsal SNpc are preferentially degenerated in A53T transgenic mice.

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ALDH1A1-negative nigrostriatal DA neurons in the dorsal SNpc are prefere...
(A) TH staining (brown) of midbrain coronal sections (top, bregma –2.90, bottom, bregma –3.20) of 18-month-old A53T and littermate nTg female mice. (B) Number of TH-positive neurons remaining in SNpc of 1-month-old (n = 3 per genotype) and 18-month-old (n = 5 per genotype) A53T and littermate nTg female mice. (C) Volume of SNpc of 18-month-old A53T and littermate nTg female mice (n = 5 per genotype). (D) Minimal distance between neighboring DA neurons in SNpc of 18-month-old A53T and littermate nTg female mice. 1,336 and 1,060 nigrostriatal DA neurons from 3 pairs of A53T and nTg mice were analyzed, respectively. (E) 3D reconstruction of TH-positive neurons distributed in SNpc, VTA, and retrorubral field (RRF) of 18-month-old A53T and control nTg female mice. Arrows point to DM tier of DA neurons in SNpc of nTg and A53T mice. D, dorsal; L, lateral; Ro, rostral. (F) Representative images show TH and ALDH1A1 staining in midbrain coronal sections (bregma –2.92) of 1- and 18-month-old A53T and 18-month-old nTg female mice. Arrowheads indicate DM ALDH1A1-negative DA neurons. Arrowheads point to the DM tier of SNpc. (G) Representative images show ALDH1A1 and TH staining in DA neurons of 1-month-old A53T nTg mice. (H) Numbers of TH-positive/ALDH1A1-positive DA neurons and (I) TH-positive/ALDH1A1-negative DA neurons remaining in SNpc of 1-month-old (n = 3 per genotype) and 18-month-old (n = 5 per genotype) A53T and nTg female mice. (J–L) Numbers of total (J) TH-positive, (K) TH-positive/ALDH1A1-positive, and (L) TH-positive/ALDH1A1-negative DA neurons remaining in VTA of 1-month-old (n = 3 per genotype) and 18-month-old (n = 5 per genotype) A53T and nTg female mice. Scale bar: 100 μm (A and F); 20 μm (G). (A and F) The dashed line marks the boundary between SNpc and VTA. *P < 0.05, **P < 0.01, ***P < 0.001.