ArticleProceedings of the National Academy of Sciences of the United States of America2019
Ubiquitin C-terminal hydrolase L1 (UCH-L1) loss causes neurodegeneration by altering protein turnover in the first postnatal weeks.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed.
- Decode the Ubiquitinome in Parkinson's Disease: From Pathological Aggregates to Targeted DUB Therapeutics.Neuroscience bulletin · 2026Review
- Ketogenic diet regulates Uch-L1(C) to improve cerebral energy metabolism and cognitive function in Alzheimer's disease mice.European journal of histochemistry : EJH · 2026Article
- Fine-Tuning Protein Fate: Mechanisms of E1, E2, and E3 Enzymes and Deubiquitinases in Cell Signaling.International journal of molecular sciences · 2026Review
- Article
- Ubiquitination in the Nervous System: From Molecular Mechanisms to Disease Implications.Molecular neurobiology · 2025Review
- Critical roles ofLife science alliance · 2025Article
- The Life of a Kidney Podocyte.Acta physiologica (Oxford, England) · 2025Review
- Article
- Plasma biomarkers in chronic single moderate-severe traumatic brain injury.Brain : a journal of neurology · 2024Article
- Abolishing UCHL1's hydrolase activity exacerbates ischemia-induced axonal injury and functional deficits in mice.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2024Article
- A novel proteomic signature of osteoclast differentiation unveils the deubiquitinase UCHL1 as a necessary osteoclastogenic driver.Scientific reports · 2024Article
- Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis.Nature communications · 2023Article
- Role of UCHL1 in the pathogenesis of neurodegenerative diseases and brain injury.Ageing research reviews · 2023Review
- Antidiabetic Drugs Can Reduce the Harmful Impact of Chronic Smoking on Post-Traumatic Brain Injuries.International journal of molecular sciences · 2023Article
- Podocyte-specific deletion of ubiquitin carboxyl-terminal hydrolase L1 causes podocyte injury by inducing endoplasmic reticulum stress.Cellular and molecular life sciences : CMLS · 2023Article
- Stepwise fate conversion of supporting cells to sensory hair cells in the chick auditory epithelium.iScience · 2023Article
- Elevated biomarkers of neural injury in older adults following head-down bed rest: links to cardio-postural deconditioning with spaceflight and aging.Frontiers in human neuroscience · 2023Article
- Role of the deubiquitinating enzyme UCH-L1 in mitochondrial function.Frontiers in cellular neuroscience · 2023Article
- Osteopontin depletion in macrophages perturbs proteostasisFrontiers in immunology · 2023Article
- The DUB Club: Deubiquitinating Enzymes and Neurodevelopmental Disorders.Biological psychiatry · 2022Review
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15 authors.
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No grant is acknowledged in the PubMed record.
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.
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