TY - JOUR
T1 - ASL expression in ALDH1A1+ neurons in the substantia nigra metabolically contributes to neurodegenerative phenotype
AU - Members of the UCDC
AU - Lerner, Shaul
AU - Eilam, Raya
AU - Adler, Lital
AU - Baruteau, Julien
AU - Kreiser, Topaz
AU - Tsoory, Michael
AU - Brandis, Alexander
AU - Mehlman, Tevie
AU - Ryten, Mina
AU - Botia, Juan A.
AU - Ruiz, Sonia Garcia
AU - Garcia, Alejandro Cisterna
AU - Dionisi-Vici, Carlo
AU - Ranucci, Giusy
AU - Spada, Marco
AU - Mazkereth, Ram
AU - McCarter, Robert
AU - Izem, Rima
AU - Balmat, Thomas J.
AU - Richesson, Rachel
AU - Baumgartner, Matthias R.
AU - Bedoyan, Jirair K.
AU - Berry, Gerard
AU - Berry, Susan A.
AU - Burgard, Peter
AU - Burrage, Lindsay
AU - Coughlin, Curtis
AU - Diaz, George A.
AU - Enns, Gregory
AU - Gallagher, Renata C.
AU - Gropman, Andrea
AU - Harding, Cary O.
AU - Hoffmann, Georg
AU - Le Mons, Cynthia
AU - McCandless, Shawn E.
AU - Merritt, J. Lawrence
AU - Schulze, Andreas
AU - Seminara, Jennifer
AU - Stricker, Tamar
AU - Tuchman, Mendel
AU - Waisbren, Susan
AU - Weisfeld-Adams, James D.
AU - Wong, Derek
AU - Yudkoff, Marc
AU - Gazit, Ehud
AU - Nagamani, Sandesh C.S.
AU - Erez, Ayelet
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85117434375&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85117434375&partnerID=8YFLogxK
U2 - 10.1007/s00439-021-02345-5
DO - 10.1007/s00439-021-02345-5
M3 - Article
C2 - 34417872
AN - SCOPUS:85117434375
SN - 0340-6717
VL - 140
SP - 1471
EP - 1485
JO - Human genetics
JF - Human genetics
IS - 10
ER -