Publication Date:
2013-03-05
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756911/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756911/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Hong Joo -- Kim, Nam Chul -- Wang, Yong-Dong -- Scarborough, Emily A -- Moore, Jennifer -- Diaz, Zamia -- MacLea, Kyle S -- Freibaum, Brian -- Li, Songqing -- Molliex, Amandine -- Kanagaraj, Anderson P -- Carter, Robert -- Boylan, Kevin B -- Wojtas, Aleksandra M -- Rademakers, Rosa -- Pinkus, Jack L -- Greenberg, Steven A -- Trojanowski, John Q -- Traynor, Bryan J -- Smith, Bradley N -- Topp, Simon -- Gkazi, Athina-Soragia -- Miller, Jack -- Shaw, Christopher E -- Kottlors, Michael -- Kirschner, Janbernd -- Pestronk, Alan -- Li, Yun R -- Ford, Alice Flynn -- Gitler, Aaron D -- Benatar, Michael -- King, Oliver D -- Kimonis, Virginia E -- Ross, Eric D -- Weihl, Conrad C -- Shorter, James -- Taylor, J Paul -- 089701/Wellcome Trust/United Kingdom -- AG031867/AG/NIA NIH HHS/ -- AG032953/AG/NIA NIH HHS/ -- DP2OD002177/OD/NIH HHS/ -- G0900688/Medical Research Council/United Kingdom -- K02 AG042095/AG/NIA NIH HHS/ -- MC_G1000733/Medical Research Council/United Kingdom -- NS053825/NS/NINDS NIH HHS/ -- NS067354/NS/NINDS NIH HHS/ -- P01 AG032953/AG/NIA NIH HHS/ -- R01 AG031867/AG/NIA NIH HHS/ -- R01 NS053825/NS/NINDS NIH HHS/ -- England -- Nature. 2013 Mar 28;495(7442):467-73. doi: 10.1038/nature11922. Epub 2013 Mar 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38120, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23455423" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Sequence
;
Amyotrophic Lateral Sclerosis/*genetics/metabolism/*pathology
;
Animals
;
Drosophila melanogaster/cytology/genetics/metabolism
;
Female
;
Frontotemporal Dementia/*genetics/metabolism/pathology
;
HeLa Cells
;
Heterogeneous-Nuclear Ribonucleoprotein Group A-B/*chemistry/genetics/*metabolism
;
Humans
;
Inclusion Bodies/genetics/metabolism/pathology
;
Male
;
Mice
;
Molecular Sequence Data
;
Muscular Dystrophies, Limb-Girdle/*genetics/metabolism/pathology
;
Mutant Proteins/chemistry/*genetics/metabolism
;
Mutation/*genetics
;
Myositis, Inclusion Body/*genetics/metabolism/pathology
;
Osteitis Deformans/*genetics/metabolism/pathology
;
Peptide Termination Factors/chemistry/genetics/metabolism
;
Prions/*chemistry/genetics/metabolism
;
Protein Structure, Tertiary/genetics
;
RNA/metabolism
;
Saccharomyces cerevisiae Proteins/chemistry/genetics/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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