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.
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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 3

ALDH1A1-positive DA neurons exhibit a conserved topographic distribution in human SNpc and show reduction of ALDH1A1 expression in PD.

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ALDH1A1-positive DA neurons exhibit a conserved topographic distributio...
(A) Representative bright-field image shows ALDH1A1 staining (purple) in SNpc transverse sections of control human brains. Nigrostriatal DA neurons (dark brown) were marked by the presence of NM in the soma. Arrow points to a cluster of ALDH1A1-negative DA neurons in the dorsal tier of SNpc. Arrowhead indicates a group of ALDH1A1-positive DA neurons in the ventral tier of SNpc. (B) Representative fluorescent images show TH and ALDH1A1 costaining in the transverse section of SNpc in control human brains. (C) 3D reconstruction of DA neurons in human SNpc shows the distribution of ALDH1A1 and NM double-positive (purple) as well as ALDH1A1-negative/NM-positive (brown) neurons remaining in the SNpc of control (Ctrl) and PD human brains. (D) Sketch of transverse section of human SNpc. RN, red nucleus. (E–I) Remaining DA neurons in the (E) SNpc, (F) dorsal, (G) PL, (H) VM, and (I) VL parts of control (n = 9) and PD (n = 10) brains. Numbers over the PD bars show the percentage of DA neuron loss compared with the controls. (J and K) Percentages of ALDH1A1+/NM+ and ALDH1A1–/NM+ DA neurons in SNpc, dorsal, PL, VM, and VL parts of (J) control human (n = 9) and (K) PD cases (n = 10). (L) Percentages of ALDH1A1+/NM+ and ALDH1A1–/NM+ DA neurons in SNpc, dorsal, PL, VM, and VL parts of control (n = 9) and PD cases (n = 10). (M–P) Total number and percentage of ALDH1A1+ and ALDH1A1–/NM+ neurons in the (M and N) SNpc and (O and P) VL subregion of control, mild, moderate, and severe PD cases. Scale bar: 70 μm (A); 100 μm (B). *P < 0.05, **P < 0.01, ***P < 0.001.