Journal Article
ASL expression in ALDH1A1+ neurons in the substantia nigra metabolically contributes to neurodegenerative phenotype
Shaul Lerner; Raya Eilam; Lital Adler; Julien Baruteau; Topaz Kreiser; Michael Tsoory; Alexander Brandis; Tevie Mehlman; Mina Ryten; Juan A. Botia; Sonia Garcia Ruiz; Alejandro Cisterna Garcia; Carlo Dionisi-Vici; Giusy Ranucci; Marco Spada; Ram Mazkereth; Robert McCarter; Rima Izem; Thomas J. Balmat; Rachel Richesson; Matthias R. Baumgartner; Jirair K. Bedoyan; Gerard Berry; Susan A. Berry; Peter Burgard; Lindsay Burrage; Curtis Coughlin; George A. Diaz; Gregory Enns; Renata C. Gallagher; Andrea Gropman; Cary O. Harding; Georg Hoffmann; Cynthia Le Mons; Shawn E. McCandless; J. Lawrence Merritt; Sandesh C. S. Nagamani; Andreas Schulze; Jennifer Seminara; Tamar Stricker; Mendel Tuchman; Susan Waisbren; James D. Weisfeld-Adams; Derek Wong; Marc Yudkoff; Ehud Gazit; Sandesh C. S. Nagamani; Ayelet Erez
Human Genetics · Vol. 140, Issue 10 · pp. 1471-1485 · 2021
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 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.