ASL expression in ALDH1A1⁺ neurons in the substantia nigra metabolically contributes to neurodegenerative phenotype.

ABSTRACT: Argininosuccinate lyase (ASL) is essential for the NO-dependent regulation of tyrosine hydroxylase (TH) and thus for catecholamine production. Using a conditional mouse model with loss of ASL in catecholamine neurons, we demonstrate that ASL is expressed in dopaminergic neurons in the substantia nigra pars compacta, including the ALDH1A1⁺ subpopulation that is pivotal for the pathogenesis of Parkinson disease (PD). Neuronal loss of ASL results in catecholamine deficiency, in accumulation and formation of tyrosine aggregates, in elevation of α-synuclein, and phenotypically in motor and cognitive deficits. NO supplementation rescues the formation of aggregates as well as the motor deficiencies. Our data point to a potential metabolic link between accumulations of tyrosine and see

SUBMITTER: Lerner S 

PROVIDER: S-EPMC8460544 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature