Protecting neurons in Parkinson’s disease

A defining characteristic of Parkinson’s disease (PD) is the prominent degeneration and loss of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNpc); however, it is not clear why this population of DA neurons is preferentially targeted in PD. Using a transgenic murine PD model, Guoxiang Liu and colleagues at the National Institutes of Health identified a subpopulation of SNpc DA neurons lacking aldehyde dehydrogenase 1 (ALDH1A1) that are especially prone to degeneration and accumulation of cytotoxic levels of α-synuclein. Evaluation of PD patient and healthy brains revealed a reduction ALDH1A1 expression and reduced numbers of ALDH1A1-expressing DA neurons in the SNpc of PD patients. In PD mice, deletion of Aldh1a1 exacerbated both the loss of DA neurons and α-synuclein aggregation. Expression of ALDH1A1 in cultured DA neurons from PD mice enhanced cell survival, preventing caspase-mediated cell death. This study suggests that reduced ALDH1A1 expression in PD DA neurons renders this population vulnerable to α-synuclein-mediated degeneration. The accompanying 3D reconstruction shows the distribution of DA neurons in the SNpc (red), ventral tegmental area (green), and retrorubral field (blue) of 18-month-old PD mice (left) and control mice (right). Notice the reduction of DA neurons in the dorsomedial tier of the PD SNpc.

Published May 27, 2014, by Corinne Williams

Related articles

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 Article has an altmetric score of 29

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

×
Advertisement