title: 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.forename: Guoxiang
authors.initials: G
authors.lastname: Liu
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.forename: Jinhui
authors.initials: J
authors.lastname: Ding
authors.forename: Chengsong
authors.initials: C
authors.lastname: Xie
authors.forename: Lixin
authors.initials: L
authors.lastname: Sun
authors.forename: Iakov
authors.initials: I
authors.lastname: Rudenko
authors.forename: Wang
authors.initials: W
authors.lastname: Zheng
authors.forename: Namratha
authors.initials: N
authors.lastname: Sastry
authors.forename: Jing
authors.initials: J
authors.lastname: Luo
authors.forename: Gay
authors.initials: G
authors.lastname: Rudow
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.forename: Huaibin
authors.initials: H
authors.lastname: Cai
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000145:classification / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050697:Retinal Dehydrogenase; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology*; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D011994:Recombinant Proteins; D051844:alpha-Synuclein; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase