title: Stress granules at the intersection of autophagy and ALS.
abstract: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease caused by loss of upper and lower motor neurons. The majority of ALS cases are classified as sporadic (80-90%), with the remaining considered familial based on patient history. The last decade has seen a surge in the identification of ALS-causing genes - including TARDBP (TDP-43), FUS, MATR3 (Matrin-3), C9ORF72 and several others - providing important insights into the molecular pathways involved in pathogenesis. Most of the protein products of ALS-linked genes fall into two functional categories: RNA-binding/homeostasis and protein-quality control (i.e. autophagy and proteasome). The RNA-binding proteins tend to be aggregation-prone with low-complexity domains similar to the prion-forming domains of yeast. Many also incorporate into stress granules (SGs), which are cytoplasmic ribonucleoprotein complexes that form in response to cellular stress. Mutant forms of TDP-43 and FUS perturb SG dynamics, lengthening their cytoplasmic persistence. Recent evidence suggests that SGs are regulated by the autophagy pathway, suggesting a unifying connection between many of the ALS-linked genes. Persistent SGs may give rise to intractable aggregates that disrupt neuronal homeostasis, thus failure to clear SGs by autophagic processes may promote ALS pathogenesis. This article is part of a Special Issue entitled SI:Autophagy.
authors.affiliation: Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Monahan
authors.affiliation: Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Shewmaker
authors.affiliation: Department of Pediatrics, Division of Child Neurology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, United States; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States. Electronic address: udai@pitt.edu.
authors.forename: Udai Bhan
authors.initials: UB
authors.lastname: Pandey
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D000073885:C9orf72 Protein; D018797:Cell Cycle Proteins / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism; D006801:Humans; D026901:Membrane Transport Proteins; D034521:Nuclear Matrix-Associated Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D035582:Transcription Factor TFIIIA / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism; D000074405:Valosin Containing Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C518587:MATR3 protein, human; D026901:Membrane Transport Proteins; D034521:Nuclear Matrix-Associated Proteins; C409460:OPTN protein, human; D011506:Proteins; D034702:RNA-Binding Protein FUS; D016601:RNA-Binding Proteins; C000598624:TARDBP protein, human; D035582:Transcription Factor TFIIIA; C405662:UBQLN2 protein, human; D014452:Ubiquitins; C439768:hnRNP A2; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein
keywords: Amyotrophic lateral sclerosis; Autophagy; Motor neuron diseases; Neurodegeneration; Neuromuscular diseases; P-bodies; Protein degradation pathways; Rapamycin; Stress granules