Neuronal cytoplasmic inclusions in tau, TDP-43, and FUS molecular subtypes of frontotemporal lobar degeneration share similar spatial patterns

Armstrong, Richard A.

doi:10.5114/fn.2017.70482

Cited by 10 publications

(7 citation statements)

References 43 publications

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“…Two mechanisms were proposed to explain FUS-related neurodegeneration. First of all, there is the toxic gain-of-function in which nuclear FUS aggregates in cytoplasm and spreads in a prion-like manner through neuronal tissues (Armstrong, 2017). Second, the depletion of FUS from the nucleus may impair transcription, alternative splicing, and DNA repair (Shang and Huang, 2016).…”

Section: Fused In Sarcoma (Fus)mentioning

confidence: 99%

The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

et al. 2020

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two diseases that form a broad neurodegenerative continuum. Considerable effort has been made to unravel the genetics of these disorders, and, based on this work, it is now clear that ALS and FTD have a significant genetic overlap. TARDBP, SQSTM1, VCP, FUS, TBK1, CHCHD10, and most importantly C9orf72, are the critical genetic players in these neurological disorders. Discoveries of these genes have implicated autophagy, RNA regulation, and vesicle and inclusion formation as the central pathways involved in neurodegeneration. Here we provide a summary of the significant genes identified in these two intrinsically linked neurodegenerative diseases and highlight the genetic and pathological overlaps.

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Section: Fused In Sarcoma (Fus)mentioning

confidence: 99%

The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

et al. 2020

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“…The clinical presentation likely depends on the specific type of neurons that are affected. Biophysical and histological analysis suggest that FUS cytoplasmic aggregation may spread across anatomical networks through a prion-like mechanism [ 6 ]. Therefore, future drugs may target FUS’s ability to cytoplasmically localize and/or form proteinaceous aggregates.…”

Section: The Link Between Fus and Neurodegenerative Diseasementioning

confidence: 99%

“…In ALS, this happens in motor neurons; the specific pathological protein may be FUS, TDP-43, SOD1 or one of several other proteins [ 89 ]. Patient pathology follows not from aggregation occurring in an isolated cell, but through entire neural networks [ 6 ]. This pattern of pathology suggests propagation through physical contact, much like prion protein (PrP), whose pathological conformation spreads through tissue in the fatal transmissible spongiform encephalopathies.…”

Section: Fus Structure and Functionmentioning

confidence: 99%

The Role of Post-Translational Modifications on Prion-Like Aggregation and Liquid-Phase Separation of FUS

Rhoads

Monahan

Yee

et al. 2018

IJMS

104

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Subcellular mislocalization and aggregation of the human FUS protein occurs in neurons of patients with subtypes of amyotrophic lateral sclerosis and frontotemporal dementia. FUS is one of several RNA-binding proteins that can functionally self-associate into distinct liquid-phase droplet structures. It is postulated that aberrant interactions within the dense phase-separated state can potentiate FUS's transition into solid prion-like aggregates that cause disease. FUS is post-translationally modified at numerous positions, which affect both its localization and aggregation propensity. These modifications may influence FUS-linked pathology and serve as therapeutic targets. Keywords: FUS; ALS; FTLD; prion; amyloid; LLPS The Link between FUS and Neurodegenerative DiseaseFUS (fused in sarcoma) gets its name from forming oncogenic fusion proteins with specific transcription factors following chromosomal rearrangements [1]. Such rearrangement is common in liposarcomas, thus FUS also goes by the name TLS (translocated in liposarcoma). Since 2009, FUS has received more attention for its connection to neurodegenerative disease after missense mutations were discovered to cause a small percentage of cases of amyotrophic lateral sclerosis (ALS-FUS) [2,3]. In the motor neurons of these patients, the normally nuclear FUS protein was found in cytoplasmic proteinaceous inclusions. Since then, non-mutant FUS has been identified in cytoplasmic inclusions in cortical neurons of a subset of patients with frontotemporal dementia (FTD; the neuropathological diagnosis is termed frontotemporal lobar degeneration (FTLD-FUS)) [4]. Both ALS and FTD are incurable and their clinical and pathological overlap suggests that they are part of a disease continuum.Mutations in FUS are autosomal dominant causes of familial ALS. Most mutations alter the C-terminal nuclear localization signal, resulting in excess cytoplasmic FUS that can form inclusions with gain-of-function toxicity [5]. Whether ALS-FUS or FTLD-FUS, it is the accumulation of FUS into cytoplasmic aggregates that appears to cause neuronal loss. The clinical presentation likely depends on the specific type of neurons that are affected. Biophysical and histological analysis suggest that FUS cytoplasmic aggregation may spread across anatomical networks through a prion-like mechanism [6]. Therefore, future drugs may target FUS's ability to cytoplasmically localize and/or form proteinaceous aggregates. Extensive post-translational methylation and phosphorylation of FUS have been shown to influence localization and aggregation, respectively. Here we review the post-translational modifications (PTMs) of FUS in the context of how they affect function, self-association and pathology.

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“…, 2009 ). Cellular pathology follows along neuroanatomical pathways, suggesting “prionlike” spread of protein aggregates ( Armstrong, 2017 ). Cytoplasmic FUS inclusions are proposed to have an emergent gain-of-function toxicity ( Sharma et al.…”

Section: Introductionmentioning

confidence: 99%

The prionlike domain of FUS is multiphosphorylated following DNA damage without altering nuclear localization

Rhoads

Monahan

Yee

et al. 2018

MBoC

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FUS (fused in sarcoma) is an abundant, predominantly nuclear protein involved in RNA processing. Under various conditions, FUS functionally associates with RNA and other macromolecules to form distinct, reversible phase-separated liquid structures. Persistence of the phase-separated state and increased cytoplasmic localization are both hypothesized to predispose FUS to irreversible aggregation, which is a pathological hallmark of subtypes of amyotrophic lateral sclerosis and frontotemporal dementia. We previously showed that phosphorylation of FUS’s prionlike domain suppressed phase separation and toxic aggregation, proportionally to the number of added phosphates. However, phosphorylation of FUS’s prionlike domain was previously reported to promote its cytoplasmic localization, potentially favoring pathological behavior. Here we used mass spectrometry and human cell models to further identify phosphorylation sites within FUS’s prionlike domain, specifically following DNA-damaging stress. In total, 28 putative sites have been identified, about half of which are DNA-dependent protein kinase (DNA-PK) consensus sites. Custom antibodies were developed to confirm the phosphorylation of two of these sites (Ser-26 and Ser-30). Both sites were usually phosphorylated in a subpopulation of cellular FUS following a variety of DNA-damaging stresses but not necessarily equally or simultaneously. Importantly, we found DNA-PK–dependent multiphosphorylation of FUS’s prionlike domain does not cause cytoplasmic localization.

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Neuronal cytoplasmic inclusions in tau, TDP-43, and FUS molecular subtypes of frontotemporal lobar degeneration share similar spatial patterns

Cited by 10 publications

References 43 publications

The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

The Role of Post-Translational Modifications on Prion-Like Aggregation and Liquid-Phase Separation of FUS

The prionlike domain of FUS is multiphosphorylated following DNA damage without altering nuclear localization

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