Expanded polyglutamine impairs normal nuclear distribution of fused in sarcoma and poly (rC)‐binding protein 1 in Huntington's disease

Mori, Shinichiro; Honda, Hiroki; Ishii, Takashi; Yoshimura, M.; Sasagasako, Naokazu; Suzuki, Satoshi; Taniwaki, Takayuki; Iwaki, Toru

doi:10.1111/neup.12600

Cited by 15 publications

(11 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…FUS pathology also defines a subset of cases with FTD (FTD-FUS) with prominent atrophy of the caudate putamen 24 – 26 , concomitant pathology of other FET proteins, such as TAF15 and EWSR1 12 , 27 – 30 and frequent psychiatric symptoms 28 . FUS aggregates have also been observed in spinocerebellar ataxia and Huntington’s disease 31 , 32 . While FUS mislocalization appears to be a common feature in neurodegenerative diseases, its pathological consequences have not been thoroughly studied beyond motor neuron degeneration.…”

Section: Introductionmentioning

confidence: 97%

Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects

et al. 2021

View full text Add to dashboard Cite

Gene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives behavioral abnormalities in knock-in mice, including locomotor hyperactivity and alterations in social interactions, in the absence of widespread neuronal loss. Mechanistically, we identified a progressive increase in neuronal activity in the frontal cortex of Fus knock-in mice in vivo, associated with altered synaptic gene expression. Synaptic ultrastructural and morphological defects were more pronounced in inhibitory than excitatory synapses and associated with increased synaptosomal levels of FUS and its RNA targets. Thus, cytoplasmic FUS triggers synaptic deficits, which is leading to increased neuronal activity in frontal cortex and causing related behavioral phenotypes. These results indicate that FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, likely relevant also for other neurodegenerative diseases characterized by FUS mislocalization.

show abstract

Section: Introductionmentioning

confidence: 97%

Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Besides FUS -ALS, FUS mutations have been associated with other neurodegenerative diseases, such as frontotemporal dementia [ 33 – 35 ], chorea [ 36 ], mental retardation [ 37 ], psychosis [ 38 ] and essential tremor [ 39 ]. FUS aggregation has been observed in sporadic ALS [ 40 – 42 ] and FTD [ 43 – 45 ], but also in spino-cerebellar ataxia and Huntington’s disease [ 46 , 47 ]. A gene therapy to restore normal nuclear FUS levels might thus be relevant for other patients to be identified.…”

Section: Discussionmentioning

confidence: 99%

Wild-type FUS corrects ALS-like disease induced by cytoplasmic mutant FUS through autoregulation

Sanjuan-Ruiz

Govea-Perez

McAlonis-Downes

et al. 2021

Mol Neurodegeneration

View full text Add to dashboard Cite

Mutations in FUS, an RNA-binding protein involved in multiple steps of RNA metabolism, are associated with the most severe forms of amyotrophic lateral sclerosis (ALS). Accumulation of cytoplasmic FUS is likely to be a major culprit in the toxicity of FUS mutations. Thus, preventing cytoplasmic mislocalization of the FUS protein may represent a valuable therapeutic strategy. FUS binds to its own pre-mRNA creating an autoregulatory loop efficiently buffering FUS excess through multiple proposed mechanisms including retention of introns 6 and/or 7. Here, we introduced a wild-type FUS gene allele, retaining all intronic sequences, in mice whose heterozygous or homozygous expression of a cytoplasmically retained FUS protein (Fus∆NLS) was previously shown to provoke ALS-like disease or postnatal lethality, respectively. Wild-type FUS completely rescued the early lethality caused by the two Fus∆NLS alleles, and improved the age-dependent motor deficits and reduced lifespan caused by heterozygous expression of mutant FUS∆NLS. Mechanistically, wild-type FUS decreased the load of cytoplasmic FUS, increased retention of introns 6 and 7 in the endogenous mouse Fus mRNA, and decreased expression of the mutant mRNA. Thus, the wild-type FUS allele activates the homeostatic autoregulatory loop, maintaining constant FUS levels and decreasing the mutant protein in the cytoplasm. These results provide proof of concept that an autoregulatory competent wild-type FUS expression could protect against this devastating, currently intractable, neurodegenerative disease.

show abstract

“…neurodegenerative diseases, such as frontotemporal dementia 27,28,29 , chorea 30 , mental retardation 31 , psychosis 32 and essential tremor 33 . FUS aggregation has been observed in sporadic ALS [34][35][36] and FTD [37][38][39] , but also in spino-cerebellar ataxia and Huntington's disease 40,41 . A gene therapy to restore normal nuclear FUS levels might thus be relevant for other patients to be identified.…”

Section: Fus-als Besides Fus-als Fus Mutations Have Been Associatedmentioning

confidence: 99%

Wild-type FUS corrects ALS-like disease induced by cytoplasmic mutant FUS through autoregulation

Sanjuan-Ruiz

Govea-Perez

McAlonis-Downes

et al. 2020

Preprint

View full text Add to dashboard Cite

Mutations in FUS, an RNA-binding protein involved in multiple steps of RNA metabolism, are associated with the most severe forms of amyotrophic lateral sclerosis (ALS). Accumulation of cytoplasmic FUS is likely to be a major culprit in the toxicity of FUS mutations. Thus, preventing cytoplasmic mislocalization of the FUS protein may represent a valuable therapeutic strategy. FUS binds to its own pre-mRNA creating an autoregulatory loop efficiently buffering FUS excess through multiple proposed mechanisms including retention of introns 6 and/or 7. Here, we introduced a wild-type FUS gene allele, retaining all intronic sequences, in mice whose heterozygous or homozygous expression of a cytoplasmically retained FUS protein (FusΔNLS) was previously shown to provoke ALS-like disease or postnatal lethality, respectively. Wild-type FUS completely rescued the early lethality caused by the two FusΔNLS alleles, and improved age-dependent motor deficit and reduced lifespan associated with the heterozygous expression of FusΔNLS. Mechanistically, wild-type FUS decreased the load of cytoplasmic FUS, increased exon 7 skipping and retention of introns 6 and 7 in the endogenous mouse Fus mRNA, leading to decreased expression of the mutant mRNA. Thus, the wild-type FUS allele activates the homeostatic autoregulatory loop, maintaining constant FUS levels and decreasing the mutant protein in the cytoplasm. These results provide proof of concept that an autoregulatory competent wild-type FUS expression could protect against this devastating, currently intractable, neurodegenerative disease.

show abstract

Expanded polyglutamine impairs normal nuclear distribution of fused in sarcoma and poly (rC)‐binding protein 1 in Huntington's disease

Cited by 15 publications

References 33 publications

Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects

Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects

Wild-type FUS corrects ALS-like disease induced by cytoplasmic mutant FUS through autoregulation

Wild-type FUS corrects ALS-like disease induced by cytoplasmic mutant FUS through autoregulation

Contact Info

Product

Resources

About