title: An acetylation switch controls TDP-43 function and aggregation propensity.
abstract: TDP-43 pathology is a disease hallmark that characterizes amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). Although a critical role for TDP-43 as an RNA-binding protein has emerged, the regulation of TDP-43 function is poorly understood. Here, we identify lysine acetylation as a novel post-translational modification controlling TDP-43 function and aggregation. We provide evidence that TDP-43 acetylation impairs RNA binding and promotes accumulation of insoluble, hyper-phosphorylated TDP-43 species that largely resemble pathological inclusions in ALS and FTLD-TDP. Moreover, biochemical and cell-based assays identify oxidative stress as a signalling cue that promotes acetylated TDP-43 aggregates that are readily engaged by the cellular defense machinery. Importantly, acetylated TDP-43 lesions are found in ALS patient spinal cord, indicating that aberrant TDP-43 acetylation and loss of RNA binding are linked to TDP-43 proteinopathy. Thus, modulating TDP-43 acetylation represents a plausible strategy to fine-tune TDP-43 activity, which could provide new therapeutic avenues for TDP-43 proteinopathies.
authors.affiliation: Department of Neurology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, 115 Mason Farm Road, NRB 6109A, CB #7250, Chapel Hill, North Carolina 27599, USA.
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Cohen
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, 3600 Spruce Street, 3rd Fl Maloney Building, Philadelphia Pennsylvania 19104, USA.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Hwang
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, 3600 Spruce Street, 3rd Fl Maloney Building, Philadelphia Pennsylvania 19104, USA.
authors.forename: Clark R
authors.initials: CR
authors.lastname: Restrepo
authors.affiliation: Department of Pharmacology, University of Pennsylvania School of Medicine, 838 Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Chao-Xing
authors.initials: CX
authors.lastname: Yuan
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, 3600 Spruce Street, 3rd Fl Maloney Building, Philadelphia Pennsylvania 19104, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, 3600 Spruce Street, 3rd Fl Maloney Building, Philadelphia Pennsylvania 19104, USA.
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000107:Acetylation; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008239:Lysine / Q000378:metabolism*; D013058:Mass Spectrometry; D016297:Mutagenesis, Site-Directed; D018384:Oxidative Stress / Q000502:physiology; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000473:pathology
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C000598624:TARDBP protein, human; D008239:Lysine