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

doi:10.1007/s00439-021-02345-5

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

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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.

Original language	English
Pages (from-to)	1471-1485
Number of pages	15
Journal	Human Genetics
Volume	140
Issue number	10
Early online date	21 Aug 2021
DOIs	https://doi.org/10.1007/s00439-021-02345-5
Publication status	Published - Oct 2021

Funding

We acknowledge and thank the Weizmann Institute for providing financial and infrastructural support. AE is supported by research grants from the European research program (ERC818943) and the Israel Science Foundation (860/18). AE received additional support from The Moross Integrated Cancer Center, Sagol Institute for Longevity Research, Adelis Foundation, Rising Tide Foundation, and Manya and Adolph Zarovinsky. Members of the UCDC include Nicholas Ah Mew, 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 II, Sandesh CS Nagamani, Andreas Schulze, Jennifer Seminara, Tamar Stricker, Mendel Tuchman, Susan Waisbren, James D. Weisfeld-Adams, Derek Wong, and Marc Yudkoff. The UCDC (U54HD061221) is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the Office of Rare Diseases Research (ORDR), the National Center for Advancing Translational Science (NCATS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The UCDC is also supported by the O'Malley Foundation, the Kettering Fund, and the National Urea Cycle Disorders Foundation. The contents of this manuscript are solely the responsibility of the authors, and they do not necessarily represent the official views of the NICHD or the National Institutes of Health. Figure 4 F was generated using BioRender.com. We acknowledge and thank the Weizmann Institute for providing financial and infrastructural support. AE is supported by research grants from the European research program (ERC818943) and the Israel Science Foundation (860/18). AE received additional support from The Moross Integrated Cancer Center, Sagol Institute for Longevity Research, Adelis Foundation, Rising Tide Foundation, and Manya and Adolph Zarovinsky. The UCDC (U54HD061221) is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the Office of Rare Diseases Research (ORDR), the National Center for Advancing Translational Science (NCATS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The UCDC is also supported by the O'Malley Foundation, the Kettering Fund, and the National Urea Cycle Disorders Foundation. The contents of this manuscript are solely the responsibility of the authors, and they do not necessarily represent the official views of the NICHD or the National Institutes of Health. Figure F was generated using BioRender.com.

All Science Journal Classification (ASJC) codes

Genetics
Genetics(clinical)

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Cite this

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title = "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 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. ",

author = "Shaul Lerner and Raya Eilam and Lital Adler and Michael Tsoory and Alexander Brandis and Ayelet Erez",

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T1 - ASL expression in ALDH1A1 + neurons in the substantia nigra metabolically contributes to neurodegenerative phenotype

AU - Lerner, Shaul

AU - Eilam, Raya

AU - Adler, Lital

AU - Tsoory, Michael

AU - Brandis, Alexander

AU - Erez, Ayelet

PY - 2021/10

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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.

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