ReviewExperimental & molecular medicine2015
Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies.
Review in Experimental & molecular medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 468 papers.
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Who cites it
468 citing papers in PubMed, 878 citations in OpenAlex.
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- Targeting innovative therapeutic approaches to the hallmarks of aging to combat Alzheimer's disease.Neural regeneration research · 2026Article
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- A multi-region transcriptomic framework reveals global and region-specific ubiquitin-proteasome system biomarkers in Alzheimer's disease.Functional & integrative genomics · 2026Article
- Convergent Astrocytic Failure in Parkinson's Disease: A System-Level Model of Pathogenesis and Treatment.Molecular neurobiology · 2026Review
- Retromer-targeted therapy for neurodegenerative diseases.Molecular neurodegeneration · 2026Review
- Elevated levels of Ube2g1 in hematopoietic stem cells lead to segmental aging of the hematopoietic system.Haematologica · 2026Article
- Lipid-conjugated Ru(iii) complexes as inhibitors of pathological peptide aggregation in neurodegenerative disorders.RSC medicinal chemistry · 2026Article
- Epigenetic aging in Alzheimer's disease: Relation to proteome.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Structural proteomics reveals that misfolded nascent proteins expose buried lysines for ubiquitination and rapid proteasomal degradation.Cell reports · 2026Article
- Review
- Microglia extract neuronal proteolytic organelles via skoupocytosis.bioRxiv : the preprint server for biology · 2026Article
- The expanding role of protease therapeutics (2012-2026): from replacement therapies to immune system modulation and beyond.The Biochemical journal · 2026Review
- Protein glycoxidation in neuropsychiatric disorders-from basic research to clinical practice.Redox biology · 2026Review
- Tightly Knotted Enzymes Inhibit Protein-Protein Aggregation.bioRxiv : the preprint server for biology · 2026Article
- The retroelement-derived human protein PEG10 is a regulator of mRNA splicing in neurons.bioRxiv : the preprint server for biology · 2026Article
- Molecular engineering of lysosome-based degraders unveils a rapidly expanding therapeutic strategy.Autophagy · 2026Review
408 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into β-sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons.
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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.