Ubiquitin C-terminal hydrolase L1 (UCH-L1) loss causes neurodegeneration by altering protein turnover in the first postnatal weeks.

Autor:	Reinicke AT; Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Laban K; Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Sachs M; Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Kraus V; Behavioral Biology, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Walden M; Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Damme M; Institute of Biochemistry, Christian Albrechts University Kiel, 24118 Kiel, Germany., Sachs W; Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Reichelt J; Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Schweizer M; Center for Molecular Neurobiology Hamburg, Morphology and Electron Microscopy, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Janiesch PC; Neuronal Translational Control Research Group, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Duncan KE; Neuronal Translational Control Research Group, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Saftig P; Institute of Biochemistry, Christian Albrechts University Kiel, 24118 Kiel, Germany., Rinschen MM; Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.; Center for Mass Spectrometry and Metabolomics, The Scripps Research Institute, La Jolla, CA 92037., Morellini F; Behavioral Biology, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Meyer-Schwesinger C; Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; c.meyer-schwesinger@uke.uni-hamburg.de.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2019 Apr 16; Vol. 116 (16), pp. 7963-7972. Date of Electronic Publication: 2019 Mar 28.
DOI:	10.1073/pnas.1812413116
Abstrakt:	Ubiquitin C-terminal hydrolase L1 (UCH-L1) is one of the most abundant and enigmatic enzymes of the CNS. Based on existing UCH-L1 knockout models, UCH-L1 is thought to be required for the maintenance of axonal integrity, but not for neuronal development despite its high expression in neurons. Several lines of evidence suggest a role for UCH-L1 in mUB homeostasis, although the specific in vivo substrate remains elusive. Since the precise mechanisms underlying UCH-L1-deficient neurodegeneration remain unclear, we generated a transgenic mouse model of UCH-L1 deficiency. By performing biochemical and behavioral analyses we can show that UCH-L1 deficiency causes an acceleration of sensorimotor reflex development in the first postnatal week followed by a degeneration of motor function starting at periadolescence in the setting of normal cerebral mUB levels. In the first postnatal weeks, neuronal protein synthesis and proteasomal protein degradation are enhanced, with endoplasmic reticulum stress, and energy depletion, leading to proteasomal impairment and an accumulation of nondegraded ubiquitinated protein. Increased protein turnover is associated with enhanced mTORC1 activity restricted to the postnatal period in UCH-L1-deficient brains. Inhibition of mTORC1 with rapamycin decreases protein synthesis and ubiquitin accumulation in UCH-L1-deficient neurons. Strikingly, rapamycin treatment in the first 8 postnatal days ameliorates the neurological phenotype of UCH-L1-deficient mice up to 16 weeks, suggesting that early control of protein homeostasis is imperative for long-term neuronal survival. In summary, we identified a critical presymptomatic period during which UCH-L1-dependent enhanced protein synthesis results in neuronal strain and progressive loss of neuronal function. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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