Pathogenesis of FUS-associated ALS and FTD: insights from rodent models

Nolan, Matthew J.; Talbot, Kevin; Ansorge, Olaf

doi:10.1186/s40478-016-0358-8

Cited by 103 publications

(88 citation statements)

References 95 publications

(146 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, mice of L-FUS transgenic line with further reduced expression level of the same truncated variant of FUS in the spinal cord do not develop motor neuron pathology and have normal lifespan. 9,10 This is consistent with results of studies of other FUS transgenic mice that showed a direct correlation between the level of transgene expression and the severity of pathological changes 27. It is feasible that the low level of mislocalised pathogenic form of FUSF I G U R E 3 Water induced grooming test.…”

supporting

confidence: 80%

Behavioural impairments in mice of a novel FUS transgenic line recapitulate features of frontotemporal lobar degeneration

Lysikova

Kukharsky

Chaprov

et al. 2019

Genes Brain and Behavior

View full text Add to dashboard Cite

Multiple clinical and experimental evidences suggest that amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are members of a disease continuum. Pathological inclusions of fused in sarcoma (FUS) protein have been observed in subsets of patients with these diseases but their anatomical distribution is different for two diseases. These structures are present in motor neurons in ALS cases but in cortical neurons in FTLD cases. Expression of a C‐terminally truncated form of human FUS causes an early onset and progressive motor neuron pathology in transgenic mice but only when these neurons express a certain level of this protein. Severe motor dysfunction and early lethality of mice with expression above this level prevent their use for studies of FTLD‐related pathology caused by expression of this form of FUS. In the present study, we used another line of mice expressing the same protein but not developing any signs of motor system dysfunction due to substantially lower level of transgene expression in motor neurons. In a set of tests 5‐month old mice displayed certain behavioural abnormalities, including increased impulsivity, decreased anxiety and compromised social interaction, which recapitulate behaviour characteristics typically seen in FTLD patients.

show abstract

supporting

confidence: 80%

Behavioural impairments in mice of a novel FUS transgenic line recapitulate features of frontotemporal lobar degeneration

Lysikova

Kukharsky

Chaprov

et al. 2019

Genes Brain and Behavior

View full text Add to dashboard Cite

show abstract

“…Of the ∼3% of ALS cases that do not have TDP-43 aggregation, FUS is analogously aggregated in ∼50% of these (Mackenzie et al 2007). However, unlike with TDP-43, FUS pathology never presents without FUS mutations, >50 of which have been described (Nolan et al 2016). Whereas disease-causing TDP-43 mutations are clustered in the C-terminal G-rich and Q/N regions, FUS mutations occur throughout the protein, although the most common and well-described are in the C-terminal NLS (Shang and Huang 2016;Svetoni et al 2016).…”

Section: Fusmentioning

confidence: 99%

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

View full text Add to dashboard Cite

Neurodegeneration is a leading cause of death in the developed world and a natural, albeit unfortunate, consequence of longer-lived populations. Despite great demand for therapeutic intervention, it is often the case that these diseases are insufficiently understood at the basic molecular level. What little is known has prompted much hopeful speculation about a generalized mechanistic thread that ties these disparate conditions together at the subcellular level and can be exploited for broad curative benefit. In this review, we discuss a prominent theory supported by genetic and pathological changes in an array of neurodegenerative diseases: that neurons are particularly vulnerable to disruption of RNA-binding protein dosage and dynamics. Here we synthesize the progress made at the clinical, genetic, and biophysical levels and conclude that this perspective offers the most parsimonious explanation for these mysterious diseases. Where appropriate, we highlight the reciprocal benefits of cross-disciplinary collaboration between disease specialists and RNA biologists as we envision a future in which neurodegeneration declines and our understanding of the broad importance of RNA processing deepens.

show abstract

“…ALS-linked mutations in FUS lead to the mislocalization of the protein to the cytoplasm from the nucleus (Munoz et al, 2009;Neumann et al, 2009;Dormann et al, 2010). Rodents and flies expressing wild type or mutant FUS developed defective phenotypes, such as synapse loss in the neuromuscular junction, aggregate formation in the cytoplasm, imbalance of mitochondrial dynamics, and mitochondrial dysfunction (Lanson Jr. et al, 2011;Altanbyek et al, 2016;Nolan et al, 2016). However, the molecular mechanisms underlying FUS-induced neuronal toxicity are not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

Parkin expression reverses mitochondrial dysfunction in fused in sarcoma‐induced amyotrophic lateral sclerosis

Choi

Kim

et al. 2019

Insect Molecular Biology

View full text Add to dashboard Cite

Fused in sarcoma (FUS) is a DNA/RNA‐binding protein associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. The exact molecular mechanisms by which FUS results in neurotoxicity have not yet been fully elucidated. Here, we found that parkin is a genetic suppressor of defective phenotypes induced by exogenous human wild type FUS in Drosophila. Although parkin overexpression did not modulate the FUS protein expression level, the locomotive defects in FUS‐expressing larvae and adult flies were rescued by parkin expression. We found that FUS expression in muscle tissues resulted in a reduction of the levels and assembly of mitochondrial complex I and III subunits, as well as decreased ATP. Remarkably, expression of parkin suppressed these mitochondrial dysfunctions. Our results indicate parkin as a neuroprotective regulator of FUS‐induced proteinopathy by recovering the protein levels of mitochondrial complexes I and III. Our findings on parkin‐mediated neuroprotection may expand our understanding of FUS‐induced ALS pathogenesis.

show abstract

Pathogenesis of FUS-associated ALS and FTD: insights from rodent models

Cited by 103 publications

References 95 publications

Behavioural impairments in mice of a novel FUS transgenic line recapitulate features of frontotemporal lobar degeneration

Behavioural impairments in mice of a novel FUS transgenic line recapitulate features of frontotemporal lobar degeneration

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

Parkin expression reverses mitochondrial dysfunction in fused in sarcoma‐induced amyotrophic lateral sclerosis

Contact Info

Product

Resources

About