ArticleAutophagy2016
Defective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLD.
Article in Autophagy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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Who cites it
86 citing papers in PubMed, 151 citations in OpenAlex.
- The central role of mitochondrial dysfunction in neurodegeneration: implications for therapy.Molecular and cellular biochemistry · 2026Review
- The SQSTM1 L341V Variant Associated With Sporadic ALS Promotes the Accumulation of Enlarged Ubiquitin-Positive SQSTM1 Bodies.Genes to cells : devoted to molecular & cellular mechanisms · 2026Article
- Targeting mtDNA to Modulate Mitochondrial Dysfunction in Neurodegenerative Diseases.Molecular neurobiology · 2026Review
- Extracellular vesicle-based targeted protein degradation platform for multiple extracellular proteins.EMBO molecular medicine · 2026Article
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- Nanoinducer-mediated mitochondria-selective degradation enhances T cell immunotherapy against multiple cancers.Nature nanotechnology · 2025Article
- Atypical Ocular Myasthenia-Like Presentation in a Patient With a Heterozygous SQSTM1 Variant.Cureus · 2025Article
- Heavy metal-induced disruption of the autophagy-lysosomal pathway: implications for aging and neurodegenerative disorders.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2025Review
- Sestrin2 ameliorates age-related spontaneous benign prostatic hyperplasia via activation of AMPK/mTOR dependent autophagy.Biogerontology · 2025Article
- Small HSPs at the crossroad between protein aggregation, autophagy and unconventional secretion: clinical implications and potential therapeutic opportunities in the context of neurodegenerative diseases.Frontiers in cell and developmental biology · 2025Review
- Mechanism of exercise-derived circulating exosomes as a target for sarcopenia management.Frontiers in physiology · 2025Review
- Novel SQSTM1 (c.838G>T) Mutation Identified in Two Unrelated Cases of Cerebellar Ataxia and Gaze Palsy.Advanced biomedical research · 2025Article
- Combined Treatment with Bojungikgi-tang (Buzhong Yiqi Decoction) and Riluzole Attenuates Cell Death in TDP-43-Expressing Cells.Chinese journal of integrative medicine · 2024Article
- Review
- Determination of hATG8 Binding Selectivity of AIM (Autophagy-Interacting Motif) Peptides Using Native Electrospray Ionization Mass Spectrometry.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Tethering ATG16L1 or LC3 induces targeted autophagic degradation of protein aggregates and mitochondria.Autophagy · 2023Article
- Review
- The Dysregulated MAD in Mad: A Neuro-theranostic Approach Through the Induction of Autophagic Biomarkers LC3B-II and ATG.Molecular neurobiology · 2023Review
- SRF deletion results in earlier disease onset in a mouse model of amyotrophic lateral sclerosis.JCI insight · 2023Article
- Review
26 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
Abstract
Growing evidence implicates impairment of autophagy as a candidate pathogenic mechanism in the spectrum of neurodegenerative disorders which includes amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS-FTLD). SQSTM1, which encodes the autophagy receptor SQSTM1/p62, is genetically associated with ALS-FTLD, although to date autophagy-relevant functional defects in disease-associated variants have not been described. A key protein-protein interaction in autophagy is the recognition of a lipid-anchored form of LC3 (LC3-II) within the phagophore membrane by SQSTM1, mediated through its LC3-interacting region (LIR), and notably some ALS-FTLD mutations map to this region. Here we show that although representing a conservative substitution and predicted to be benign, the ALS-associated L341V mutation of SQSTM1 is defective in recognition of LC3B. We place our observations on a firm quantitative footing by showing the L341V-mutant LIR is associated with a ∼3-fold reduction in LC3B binding affinity and using protein NMR we rationalize the structural basis for the effect. This functional deficit is realized in motor neuron-like cells, with the L341V mutant EGFP-mCherry-SQSTM1 less readily incorporated into acidic autophagic vesicles than the wild type. Our data supports a model in which the L341V mutation limits the critical step of SQSTM1 recruitment to the phagophore. The oligomeric nature of SQSTM1, which presents multiple LIRs to template growth of the phagophore, potentially gives rise to avidity effects which amplify the relatively modest impact of any single mutation on LC3B binding. Over the lifetime of a neuron, impaired autophagy could expose a vulnerability, which ultimately tips the balance from cell survival toward cell death.
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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.