We are happy to announce that a new publication of one of the SFB projects has been accepted.

The current results of project B3 under the direction of Prof. Meyer-Schwesinger will be presented in the journal Proceedings of the National Academy of Sciences (PNAS USA) entitled "Ubiquitin C-terminal hydrolase L1 (UCH-L1) loss causes neurodegeneration by altering protein turnover in the first postnatal weeks".
We congratulate all authors.

Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) loss causes neurodegeneration by altering protein turnover in the first postnatal weeks.
Reinicke, AT, Laban, K, Sachs M, Kraus V, Walden M, Damme M, Sachs W, Reichelt J, Schweizer M, Janiesch CP, Duncan KE, Saftig P, Rischen MM, Morellini F*, Meyer-Schwesinger C*
PNAS, 2019, accepted

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 new transgenic mouse model of UCH-L1-deficiency. By performing biochemical and behavioral analyses we can show for the first time 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 ER stress, and energy depletion, leading to proteasomal impairment and an accumulation of non-degraded 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 pre-symptomatic period during which UCH-L1-dependent enhanced protein synthesis results in neuronal strain and progressive loss of neuronal function.