Molecular epidemiological study of familial amyotrophic lateral sclerosis in Japanese population by whole-exome sequencing and identification of novel HNRNPA1 mutation

Naruse, Hiroya; Ishiura, Hiroyuki; Mitsui, Jun; Date, Hidetoshi; Takahashi, Yūji; Matsukawa, Takashi; Tanaka, Masaki; Ishii, Akiko; Tamaoka, Akira; Hokkoku, Keiichi; Sonoo, Masahiro; Segawa, Mari; Ugawa, Yoshikazu; Doi, Kouki; Yoshimura, Junichi; Morishita, Shinichi; Goto, Jun; Tsuji, Shoji

doi:10.1016/j.neurobiolaging.2017.08.030

Cited by 42 publications

(44 citation statements)

References 38 publications

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“…The ALS-linked hnRNP A1 P288A mutation resides in the NLS and shows an accumulation of hnRNP A1 protein in cytoplasm and increased SG localization. 42 We confirmed the effects of the P288A mutation in our system (Supplementary information, Fig. S5).…”

Section: Parylation and Par-binding Are Differentially Required For Csupporting

confidence: 81%

PARylation regulates stress granule dynamics, phase separation, and neurotoxicity of disease-related RNA-binding proteins

et al. 2019

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Mutations in RNA-binding proteins (RBPs) localized in ribonucleoprotein (RNP) granules, such as hnRNP A1 and TDP-43, promote aberrant protein aggregation, which is a pathological hallmark of various neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Protein posttranslational modifications (PTMs) are known to regulate RNP granules. In this study, we investigate the function of poly(ADP-ribosyl)ation (PARylation), an important PTM involved in DNA damage repair and cell death, in RNP granule-related neurodegeneration. We reveal that PARylation levels are a major regulator of the assembly-disassembly dynamics of RNP granules containing disease-related RBPs, hnRNP A1 and TDP-43. We find that hnRNP A1 can both be PARylated and bind to PARylated proteins or poly(ADP-ribose) (PAR). We further uncover that PARylation of hnRNP A1 at K298 controls its nucleocytoplasmic transport, whereas PAR-binding via the PAR-binding motif (PBM) of hnRNP A1 regulates its association with stress granules. Moreover, we reveal that PAR not only dramatically enhances the liquid-liquid phase separation of hnRNP A1, but also promotes the co-phase separation of hnRNP A1 and TDP-43 in vitro and their interaction in vivo. Finally, both genetic and pharmacological inhibition of PARP mitigates hnRNP A1-and TDP-43-mediated neurotoxicity in cell and Drosophila models of ALS. Together, our findings suggest a novel and crucial role for PARylation in regulating the dynamics of RNP granules, and that dysregulation in PARylation and PAR levels may contribute to ALS disease pathogenesis by promoting protein aggregation.

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Section: Parylation and Par-binding Are Differentially Required For Csupporting

confidence: 81%

PARylation regulates stress granule dynamics, phase separation, and neurotoxicity of disease-related RNA-binding proteins

et al. 2019

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“…Currently, more than 20 genes have been identified to be causative genes for FALS,2 and a report stated that mutations in causative genes for ALS, including C9ORF72 repeat expansion, collectively account for approximately 68% of FALS and 11% of SALS cases in populations of European ancestry 3. In our recent study, on the basis of whole-exome sequencing analysis, pathogenic mutations were identified in 41 (60.3%) of the 68 FALS families 4. In our Japanese FALS series, mutations in SOD1 are the most frequent, occurring in 39.7% of the families.…”

Section: Introductionmentioning

confidence: 84%

“…Mutational analyses of our case series were previously reported partially, which include microarray-based resequencing,11 Sanger sequencing,12–17 repeat-primed PCR analysis6 and whole-exome sequencing analysis4 in our laboratory. Initially, 509 patients with ALS and 1183 control subjects were recruited to the study.…”

Section: Methodsmentioning

confidence: 99%

Burden of rare variants in causative genes for amyotrophic lateral sclerosis (ALS) accelerates age at onset of ALS

Naruse

Ishiura

Mitsui

et al. 2018

J Neurol Neurosurg Psychiatry

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ObjectivesTo evaluate the burden of rare variants in the causative genes for amyotrophic lateral sclerosis (ALS) on the age at onset of ALS in a Japanese case series.MethodsWe conducted whole-exome sequencing analysis of 89 families with familial ALS (FALS) and 410 patients with sporadic ALS (SALS) to identify known pathogenic mutations or rare functionally predicted deleterious variants in the causative genes for ALS. Rare variants (minor allele frequency <1%) with scaled Combined Annotation-Dependent Depletion score >20 were defined as rare functionally predicted deleterious variants. The patients with ALS were classified on the basis of the number of pathogenic and/or rare functionally predicted deleterious variants, and the age at onset was compared among the classified groups.ResultsWhole-exome sequencing analysis revealed known pathogenic mutations or rare functionally predicted deleterious variants in causative genes for ALS in 56 families with FALS (62.9%) and 87 patients with SALS (21.2%). Such variants in multiple genes were identified in seven probands with FALS and eight patients with SALS. The ages at onset in the patients with ALS with multiple variants were significantly earlier than those in other patients with ALS. Even when the patients with known pathogenic mutations were excluded, a significantly earlier onset of the disease was still observed in patients with multiple rare functionally predicted deleterious variants.ConclusionsA substantial number of patients carried rare variants in multiple genes, and the burden of rare variants in the known causative genes for ALS affects the age at onset in the Japanese ALS series.

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“…Several ALS-or MSP-causative familial mutations of hnRNPA1 have been identified including D262N/V, N267S, and P288S/A [15][16][17] . In terms of Kapβ2 binding for nucleocytoplasmic transport, the complex structure of PY-NLS and Kapβ2 shows the binding of residues 263-289 with Kapβ2 8 .…”

Section: Disease-causative Hereditary Mutations In the Hnrnpa1 Lc Fibmentioning

confidence: 99%

“…The LC domain also exerts a prion-like function to mediate the amyloid aggregation of hnRNPA1, which is causative to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and multisystem proteinopathy (MSP) 7,12,[15][16][17] , and enhanced by inheritable mutations 12,15 .…”

Section: Introductionmentioning

confidence: 99%

The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure

Sun

Zhao

Xia

et al. 2020

Preprint

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Human heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) serves as a key regulating protein in RNA metabolism. Malfunction of hnRNPA1 in nucleocytoplasmic transport or dynamic phase separation leads to abnormal amyloid aggregation and neurodegeneration. The low complexity (LC) domain of hnRNPA1 drives both dynamic phase separation and amyloid aggregation. Here, we use cryoelectron microscopy to determine the amyloid fibril structure formed by hnRNPA1 LC domain. Remarkably, the structure reveals that the nuclear localization sequence of hnRNPA1 (termed PY-NLS), which is initially known to mediate the nucleocytoplamic transport of hnRNPA1 through binding with karyopherin-β2 (Kapβ2), represents the major component of the fibril core. The residues that contribute to the binding of PY-NLS with Kapβ2 also exert key molecular interactions to stabilize the fibril structure. Notably, hnRNPA1 mutations found in familial amyotrophic lateral sclerosis (ALS) and multisystem proteinopathoy (MSP) are all involved in the fibril core and contribute to fibril stability. Our work illuminate structural understandings on the pathological amyloid aggregation of hnRNPA1 and the amyloid disaggregase activity of Kapβ2, and highlights the multiple roles of PY-NLS in hnRNPA1 homeostasis.

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Molecular epidemiological study of familial amyotrophic lateral sclerosis in Japanese population by whole-exome sequencing and identification of novel HNRNPA1 mutation

Cited by 42 publications

References 38 publications

PARylation regulates stress granule dynamics, phase separation, and neurotoxicity of disease-related RNA-binding proteins

PARylation regulates stress granule dynamics, phase separation, and neurotoxicity of disease-related RNA-binding proteins

Burden of rare variants in causative genes for amyotrophic lateral sclerosis (ALS) accelerates age at onset of ALS

The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure

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