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. 2019 Apr 16;116(16):7963-7972. doi: 10.1073/pnas.1812413116. Epub 2019 Mar 28.


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.

Keywords: UCH-L1; development; mTOR; neurodegeneration; protein synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Female
  • Male
  • Mice
  • Mice, Transgenic
  • Neurodegenerative Diseases* / metabolism
  • Neurodegenerative Diseases* / physiopathology
  • Neurons / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Biosynthesis
  • TOR Serine-Threonine Kinases / metabolism
  • Ubiquitin Thiolesterase* / deficiency
  • Ubiquitin Thiolesterase* / genetics
  • Ubiquitin Thiolesterase* / physiology


  • Ubiquitin carboxyl-Terminal Hydrolase L-1, mouse
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases
  • Ubiquitin Thiolesterase
  • Proteasome Endopeptidase Complex