Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation
Guoxiang Liu, … , Juan C. Troncoso, Huaibin Cai
Guoxiang Liu, … , Juan C. Troncoso, Huaibin Cai
Published May 27, 2014
Citation Information: J Clin Invest. 2014;124(7):3032-3046. https://doi.org/10.1172/JCI72176.
View: Text | PDF
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

×

Figure 1

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

Options: View larger image (or click on image) Download as PowerPoint
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.