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

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.

A cysteine near the C-terminus of UCH-L1 is dispensable for catalytic activity but is required to promote AKT phosphorylation, eIF4F assembly, and malignant B-cell survival

“…Depletion of UCH-L1 leads to cell death in these cancers in vitro and in an orthotopic model of myeloma in mice 6–8,18,19 . Small molecule inhibition of UCH-L1 are under development 20–23 , though the progressive neurodegeneration seen in Uchl1 null mice 24–27 and in humans 28 leads some to worry that this approach may result in unacceptable neuro-toxicity. Here we describe a novel requirement for the C220 residue of UCH-L1 in supporting cell survival in malignant B-cells.…”

Deubiquitinating Enzyme UCH-L1 Promotes Dendritic Cell Antigen Cross-Presentation by Favoring Recycling of MHC Class I Molecules

“…We show that LPS-mediated upregulation of UCH-L1 begins after 4 h when protein synthesis is downregulated. We and others have shown that UCH-L1 affects protein synthesis pathways via mTORC1 activity in neurons and the brain (31,32). This has consequences for Ag processing, in particular cross-presentation, whereby UCH-L1-mediated suppression of protein synthesis activity would favor loading of exogenous Ags on recycling MHC I molecules, an important source of MHC I for cross-presentation (33-35).…”

Blood-Based Biomarkers: A Forgotten Friend of Hyperacute Ischemic Stroke

“…UCH-L1, a neuronal protein that is associated with neurodegeneration, is highly expressed in the central nervous system (CNS) and is associated with synaptic plasticity, synaptic homeostasis, and self-repair of the brain after injury (9)(10)(11). Serum UCH-L1 level was elevated after 3 and 6 h of ischemia following middle cerebral artery occlusion (MCAO) in rats, while the level in intracerebral hemorrhage (ICH) rats was unchanged (12).…”