biostudies-literatureLerner SNICHD NIH HHSEuropean Research CouncilMedical Research Council1471-1485https://www.ebi.ac.uk/biostudies/studies/S-EPMC8460544biostudies-literatureUnknown140(10)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 seeHuman geneticsASL expression in ALDH1A1<sup>+</sup> neurons in the substantia nigra metabolically contributes to neurodegenerative phenotype.PMC8460544818943MR/T008024/1U54 HD061221Balmat TJHarding COLerner SMazkereth RRuiz SGSchulze ASeminara JMcCarter RRyten MStricker TGallagher RCTuchman MWeisfeld-Adams JDWong DKreiser TBerry SABedoyan JKIzem RErez AAdler LGazit EEilam RWaisbren SCoughlin CMcCandless SESpada MGarcia ACRanucci GBaumgartner MRBerry GGropman AHoffmann GMembers of the UCDCDionisi-Vici CNagamani SCSEnns GLe Mons CMerritt JLRichesson RTsoory MBurgard PBaruteau JBrandis ABurrage LYudkoff MMehlman TBotia JADiaz GAfalseASL expression in ALDH1A1<sup>+</sup> neurons in the substantia nigra metabolically contributes to neurodegenerative phenotype.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 see2021-01-01T00:00:00Z2021 Oct2026-04-08T07:29:58.255Z2022-02-11T11:55:11.483ZS-EPMC84605443441787210.1007/s00439-021-02345-5