Defective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLD.
Alice Goode,Kevin Butler,Jed Long,James R. Cavey,Daniel Scott,Barry Shaw,Jill Sollenberger,Christopher Gell,Terje Johansen,Neil J. Oldham,Mark S. Searle,Robert Layfield +11 more
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TLDR
It is shown that although representing a conservative substitution and predicted to be benign, the ALS-associated L341V mutation of SQSTM1 is defective in recognition of LC3B, a key protein-protein interaction in autophagy which could expose a vulnerability over the lifetime of a neuron, which ultimately tips the balance from cell survival toward cell death.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.read more
Citations
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Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities
Fiona M. Menzies,Angeleen Fleming,Andrea Caricasole,Carla F. Bento,Stephen P. Andrews,Avraham Ashkenazi,Jens Füllgrabe,Anne Jackson,Maria Jimenez Sanchez,Cansu Karabiyik,Floriana Licitra,Ana Lopez Ramirez,Mariana Pavel,Claudia Puri,Maurizio Renna,Thomas Ricketts,Lars Schlotawa,Mariella Vicinanza,Hyeran Won,Ye Zhu,John Skidmore,David C. Rubinsztein +21 more
TL;DR: How autophagy upregulation may be a therapeutic strategy in a wide range of neurodegenerative conditions is described and possible pathways and druggable targets that may be suitable for this objective are considered.
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Proteasomal and Autophagic Degradation Systems.
TL;DR: This review summarizes molecular details of how proteasome and autophagy pathways are functionally interconnected in cells and indicates common principles and nodes of communication that can be therapeutically exploited.
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Amyotrophic lateral sclerosis
Eva L. Feldman,Stephen A. Goutman,Susanne Petri,Letizia Mazzini,Masha G. Savelieff,Pamela J. Shaw,Gen Sobue +6 more
TL;DR: Two possible disease-modifying therapies that can slow disease progression are available for ALS, but patient management is largely mediated by symptomatic therapies, such as the use of muscle relaxants for spasticity and speech therapy for dysarthria.
Journal ArticleDOI
Autophagy in major human diseases
Daniel J. Klionsky,Giulia Petroni,Ravi K. Amaravadi,Eric H. Baehrecke,Andrea Ballabio,Andrea Ballabio,Patricia Boya,José Manuel Bravo-San Pedro,Ken Cadwell,Francesco Cecconi,Francesco Cecconi,Augustine M.K. Choi,Augustine M.K. Choi,Mary E. Choi,Mary E. Choi,Charleen T. Chu,Patrice Codogno,Patrice Codogno,María Isabel Colombo,Ana Maria Cuervo,Vojo Deretic,Ivan Dikic,Zvulun Elazar,Eeva-Liisa Eskelinen,Gian Maria Fimia,David A. Gewirtz,Douglas R. Green,Malene Hansen,Marja Jäättelä,Terje Johansen,Gábor Juhász,Vassiliki Karantza,Claudine Kraft,Guido Kroemer,Nicholas T. Ktistakis,Sharad Kumar,Sharad Kumar,Carlos López-Otín,Kay F. Macleod,Frank Madeo,Jennifer Martinez,Alicia Meléndez,Alicia Meléndez,Noboru Mizushima,Christian Münz,Josef M. Penninger,Josef M. Penninger,Rushika M. Perera,Mauro Piacentini,Mauro Piacentini,Fulvio Reggiori,David C. Rubinsztein,Kevin M. Ryan,Junichi Sadoshima,Laura Santambrogio,Luca Scorrano,Hans-Uwe Simon,Hans-Uwe Simon,Anna Katharina Simon,Anne Simonsen,Anne Simonsen,Alexandra Stolz,Nektarios Tavernarakis,Nektarios Tavernarakis,Sharon A. Tooze,Tamotsu Yoshimori,Junying Yuan,Junying Yuan,Zhenyu Yue,Qing Zhong,Lorenzo Galluzzi,Federico Pietrocola +71 more
TL;DR: In this paper, preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.
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The role of mitochondria in amyotrophic lateral sclerosis
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References
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Serhiy Pankiv,Terje Høyvarde Clausen,Trond Lamark,Andreas Brech,Jack-Ansgar Bruun,Heidi Outzen,Aud Øvervatn,Geir Bjørkøy,Terje Johansen,Fromthe ‡ BiochemistryDepartment +9 more
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