α-synuclein is a prominent genetic causal factor in the pathogenesis of PD [
33‐
37]. A potential pathogenic interaction between cytosolic dopamine and α-synuclein has been implicated in the pathogenesis of PD [
27,
38]. One of the key pathogenic mechanisms of α-synuclein in DA neurons is to form cytotoxic protein aggregates that may impair the synthesis, uptake, and degradation of dopamine [
39‐
41]. The increased formation of cytotoxic dopamine quinones and DOPAL, on the other hand, may further promote α-synuclein aggregation through polymerization of monomeric α-synuclein [
42,
43]. This pathogenic interplay between reactive dopamine derivatives and α-synuclein aggregation may form a vicious cycle that amplifies their detrimental effects to the DA neurons [
42].
When the PD-related α-synuclein A53T missense mutation is introduced into the midbrain DA neurons, the resulting
Pitx3–tTA::tetO–A53T bigenic mice develop profound motor disabilities and robust SNpc DA neuron loss [
41]. Interestingly, the degenerated neurons are mainly distributed at the dorsal medial tier of SNpc that lack ALDH1A1 expression [
16]. Noticeably, more cytotoxic α-synuclein aggregates are present in ALDH1A1-negative population of SNpc DA neurons in the mutant mice [
16], suggesting that more DOPAL or other reactive dopamine intermediates may be present in these neurons to promote α-synuclein polymerization and aggregation [
42,
43]. By contrast, the ventral ALDH1A1-postive SNpc DA neurons contain less α-synuclein aggregates and appear to resist α-synuclein-induced neuron loss during the aging process [
16], thereby supporting the protective role of ALDH1A1 in these neurons. Correlatively, genetic deletion of
Aldh1a1 gene exacerbates α-synuclein-induced SNpc DA neuronal loss in the
Aldh1a1 knockout mice [
16]. It is necessary to point out that the subtypes of the remaining SNpc DA neurons were not defined in the
Aldh1a1-deficient mice due to a lack of molecular markers. Future studies will be required to identify additional molecular markers for different subtypes of SNpc DA neurons. To directly support the protective function of ALDH1A1 for DA neurons, over-expression of ALDH1A1 selectively ameliorates α-synuclein-induced cytotoxicity in the cultured DA neurons [
16]. It will be interesting to examine the protective role of ALDH1A1
in vivo through the overexpression of ALDH1A1 or the use of selective activators. This proposed study may pave the way for establishing ALDH1A1 as an important therapeutic target for PD.