title: Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS.
abstract: Algorithms designed to identify canonical yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbour a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here we define pathogenic mutations in PrLDs of heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and in one case of familial amyotrophic lateral sclerosis. Wild-type hnRNPA2 (the most abundant isoform of hnRNPA2B1) and hnRNPA1 show an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a 'steric zipper' motif in the PrLD, which accelerates the formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Notably, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant steric zipper motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs should therefore be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.
authors: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38120, USA.
authors: Hong Joo
authors: HJ
authors: Kim
authors: Nam Chul
authors: NC
authors: Kim
authors: Yong-Dong
authors: YD
authors: Wang
authors: Emily A
authors: EA
authors: Scarborough
authors: Jennifer
authors: J
authors: Moore
authors: Zamia
authors: Z
authors: Diaz
authors: Kyle S
authors: KS
authors: MacLea
authors: Brian
authors: B
authors: Freibaum
authors: Songqing
authors: S
authors: Li
authors: Amandine
authors: A
authors: Molliex
authors: Anderson P
authors: AP
authors: Kanagaraj
authors: Robert
authors: R
authors: Carter
authors: Kevin B
authors: KB
authors: Boylan
authors: Aleksandra M
authors: AM
authors: Wojtas
authors: Rosa
authors: R
authors: Rademakers
authors: Jack L
authors: JL
authors: Pinkus
authors: Steven A
authors: SA
authors: Greenberg
authors: John Q
authors: JQ
authors: Trojanowski
authors: Bryan J
authors: BJ
authors: Traynor
authors: Bradley N
authors: BN
authors: Smith
authors: Simon
authors: S
authors: Topp
authors: Athina-Soragia
authors: AS
authors: Gkazi
authors: Jack
authors: J
authors: Miller
authors: Christopher E
authors: CE
authors: Shaw
authors: Michael
authors: M
authors: Kottlors
authors: Janbernd
authors: J
authors: Kirschner
authors: Alan
authors: A
authors: Pestronk
authors: Yun R
authors: YR
authors: Li
authors: Alice Flynn
authors: AF
authors: Ford
authors: Aaron D
authors: AD
authors: Gitler
authors: Michael
authors: M
authors: Benatar
authors: Oliver D
authors: OD
authors: King
authors: Virginia E
authors: VE
authors: Kimonis
authors: Eric D
authors: ED
authors: Ross
authors: Conrad C
authors: CC
authors: Weihl
authors: James
authors: J
authors: Shorter
authors: J Paul
authors: JP
authors: Taylor
mesh_terms: D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006367:HeLa Cells; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D018979:Myositis, Inclusion Body / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010001:Osteitis Deformans / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010454:Peptide Termination Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011328:Prions / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D012313:RNA / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D050505:Mutant Proteins; D010454:Peptide Termination Factors; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D012313:RNA