ArticleAutophagy2014
UCHL1 deficiency exacerbates human islet amyloid polypeptide toxicity in β-cells: evidence of interplay between the ubiquitin/proteasome system and autophagy.
Article in Autophagy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
46 citing papers in PubMed, 1 synthesis or guideline pooled it, 65 citations in OpenAlex.
- Pooled it
- Physiological Implications of Pancreatic Amyloid Polypeptide Aggregation and Its Inhibition by Melatonin.International journal of molecular sciences · 2026Review
- Targeting Autophagy for Otoprotection: Translating Basic Mechanisms into Clinical Strategies.International journal of molecular sciences · 2026Review
- Article
- Morphological analysis of autophagy in axonal degeneration in gracile axonal dystrophy mice.Experimental animals · 2025Article
- The overexpression of human amylin in pancreatic β cells facilitate the appearance of amylin aggregates in the kidney contributing to diabetic nephropathy.Scientific reports · 2024Article
- Ubiquitination and Metabolic Disease.Advances in experimental medicine and biology · 2024Review
- Identification of the Shared Gene Signatures Between Alzheimer's Disease and Diabetes-Associated Cognitive Dysfunction by Bioinformatics Analysis Combined with Biological Experiment.Journal of Alzheimer's disease : JAD · 2024Article
- Inhibiting mitochondrial fission rescues degeneration in hereditary spastic paraplegia neurons.Brain : a journal of neurology · 2022Article
- Human islet amyloid polypeptide: A therapeutic target for the management of type 2 diabetes mellitus.Journal of pharmaceutical analysis · 2022Review
- UCHL1 acts as a potential oncogene and affects sensitivity of common anti-tumor drugs in lung adenocarcinoma.World journal of surgical oncology · 2022Article
- The nuclear receptor REV-ERBα is implicated in the alteration of β-cell autophagy and survival under diabetogenic conditions.Cell death & disease · 2022Article
- Molecular Mechanisms of Amylin Turnover, Misfolding and Toxicity in the Pancreas.Molecules (Basel, Switzerland) · 2022Review
- Hydrogen sulfide plays a potential alternative for the treatment of metabolic disorders of diabetic cardiomyopathy.Molecular and cellular biochemistry · 2022Review
- Parkin, an E3 Ubiquitin Ligase, Plays an Essential Role in Mitochondrial Quality Control in Parkinson's Disease.Cellular and molecular neurobiology · 2021Review
- A multitude of signaling pathways associated with Alzheimer's disease and their roles in AD pathogenesis and therapy.Medicinal research reviews · 2021Review
- A Selective Look at Autophagy in Pancreatic β-Cells.Diabetes · 2021Review
- Mechanisms of Beta-Cell Apoptosis in Type 2 Diabetes-Prone Situations and Potential Protection by GLP-1-Based Therapies.International journal of molecular sciences · 2021Review
- Deubiquitinases: Modulators of Different Types of Regulated Cell Death.International journal of molecular sciences · 2021Review
- Role of UPP pathway in amelioration of diabetes-associated complications.Environmental science and pollution research international · 2021Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The islet in type 2 diabetes mellitus (T2DM) is characterized by a deficit in β-cells and increased β-cell apoptosis attributable at least in part to intracellular toxic oligomers of IAPP (islet amyloid polypeptide). β-cells of individuals with T2DM are also characterized by accumulation of polyubiquitinated proteins and deficiency in the deubiquitinating enzyme UCHL1 (ubiquitin carboxyl-terminal esterase L1 [ubiquitin thiolesterase]), accounting for a dysfunctional ubiquitin/proteasome system. In the present study, we used mouse genetics to elucidate in vivo whether a partial deficit in UCHL1 enhances the vulnerability of β-cells to human-IAPP (hIAPP) toxicity, and thus accelerates diabetes onset. We further investigated whether a genetically induced deficit in UCHL1 function in β-cells exacerbates hIAPP-induced alteration of the autophagy pathway in vivo. We report that a deficit in UCHL1 accelerated the onset of diabetes in hIAPP transgenic mice, due to a decrease in β-cell mass caused by increased β-cell apoptosis. We report that UCHL1 dysfunction aggravated the hIAPP-induced defect in the autophagy/lysosomal pathway, illustrated by the marked accumulation of autophagosomes and cytoplasmic inclusions positive for SQSTM1/p62 and polyubiquitinated proteins with lysine 63-specific ubiquitin chains. Collectively, this study shows that defective UCHL1 function may be an early contributor to vulnerability of pancreatic β-cells for protein misfolding and proteotoxicity, hallmark defects in islets of T2DM. Also, given that deficiency in UCHL1 exacerbated the defective autophagy/lysosomal degradation characteristic of hIAPP proteotoxicity, we demonstrate a previously unrecognized role of UCHL1 in the function of the autophagy/lysosomal pathway in β-cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.