Universität zu Köln

Reinicke, Anna T., Laban, Karoline, Sachs, Marlies, Kraus, Vanessa, Walden, Michael, Demme, Markus, Sachs, Wiebke, Reichelt, Julia, Schweizer, Michaels, Janiesch, Philipp Christoph, Duncan, Kent E., Saftig, Paul, Rinschen, Markus M., Morellini, Fabio and Meyer-Schwesinger, Catherine (2019). Ubiquitin C-terminal hydrolase L1 (UCH-L1) loss causes neurodegeneration by altering protein turnover in the first postnatal weeks. Proc. Natl. Acad. Sci. U. S. A., 116 (16). S. 7963 - 7973. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

Full text not available from this repository.

Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Reinicke, Anna T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Laban, Karoline UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachs, Marlies UNSPECIFIED UNSPECIFIED UNSPECIFIED Kraus, Vanessa UNSPECIFIED UNSPECIFIED UNSPECIFIED Walden, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Demme, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachs, Wiebke UNSPECIFIED UNSPECIFIED UNSPECIFIED Reichelt, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Schweizer, Michaels UNSPECIFIED UNSPECIFIED UNSPECIFIED Janiesch, Philipp Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Duncan, Kent E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Saftig, Paul UNSPECIFIED UNSPECIFIED UNSPECIFIED Rinschen, Markus M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Morellini, Fabio UNSPECIFIED UNSPECIFIED UNSPECIFIED Meyer-Schwesinger, Catherine UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-150673
DOI:	10.1073/pnas.1812413116
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	116
Number:	16
Page Range:	S. 7963 - 7973
Date:	2019
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	0027-8424
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MTOR COMPLEX 1; PROTEASOME SYSTEM; DEGRADATION; EXPRESSION; STRESS; DEGENERATION; DISEASE; NEURONS; PATHWAY; INJURY Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15067