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 seeding of pathological aggregates in neurons as initiators for the pathological processes involved in neurodegeneration. Hence, interventions in tyrosine metabolism via regulation of NO levels may be therapeutic beneficial for the treatment of catecholamine-related neurodegenerative disorders.

精氨基琥珀酸裂解酶 (ASL) 对于酪氨酸羟化酶 (TH) 的 NO 依赖性调节至关重要，因此对于儿茶酚胺的产生至关重要。使用儿茶酚胺神经元中 ASL 缺失的条件小鼠模型，我们证明 ASL 在黑质致密部的多巴胺能神经元中表达，包括 ALDH1A1 ⁺ 对帕金森病 (PD) 的发病机制至关重要的亚群。ASL 的神经元丢失导致儿茶酚胺缺乏、酪氨酸聚集体的积累和形成、α-突触核蛋白的升高以及运动和认知缺陷的表型。NO 补充剂可以挽救聚集体的形成以及运动缺陷。我们的数据表明，酪氨酸积累与神经元中病理聚集体的播种之间存在潜在的代谢联系，作为神经变性相关病理过程的引发剂。因此，通过调节 NO 水平干预酪氨酸代谢可能对儿茶酚胺相关神经退行性疾病的治疗有益。