Cell-to-Cell Transmission of Dipeptide Repeat Proteins Linked to C9orf72 -ALS/FTD

Westergard, Thomas; Jensen, Brigid K.; Wen, Xinmei; Cai, Jingli; Kropf, Elizabeth; Iacovitti, Lorraine; Pasinelli, Piera; Trotti, Davide

doi:10.1016/j.celrep.2016.09.032

Cited by 174 publications

(180 citation statements)

References 39 publications

(70 reference statements)

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“…One possibility is that DPRs may actually disrupt cellular functions by interacting with proteins involved in membraneless organelles and cytoskeletal intermediate filaments (Lin et al 2016). DPRs may also provide a useful diagnostic biomarker (Lehmer et al 2017), and their demonstrated ability to spread between cells (Westergard et al 2016) offers a simple explanation for the observation that ALS tends to spread from a region of onset to other parts of the nervous system (Brettschneider et al 2015). However, an understanding of how expanded RNA repeats make DPRs is lacking (Freibaum and Taylor 2017).…”

Section: Rna-centric Mechanisms In C9orf72 Als-ftdmentioning

confidence: 99%

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

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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.

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Section: Rna-centric Mechanisms In C9orf72 Als-ftdmentioning

confidence: 99%

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

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“…As in previous studies,11, 14 we found that poly(GP) was detectable in CSF from presymptomatic C9orf72 expansion carriers, suggesting that DPR protein production emerges prior to neurodegeneration and that poly(GP) can be actively released from putatively healthy neurons. This notion is supported by in vitro experiments that show that DPR proteins are secreted from cultured cells 11, 29. Reports of autopsy studies in C9orf72‐ patients have also described widespread DPR protein pathology prior to the formation of TDP‐43 inclusions and neuronal loss 30, 31, 32.…”

Section: Discussionmentioning

confidence: 85%

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Meeter

Gendron

Sias

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72‐associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume.MethodsWe measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel‐wise analyses.ResultsPoly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus.InterpretationThis study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72‐associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.

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“…The most common genetic cause of ALS and frontotemporal dementia consists in an aberrant hexanucleotide repeat expansions in C9orf72 (Guerreiro et al, 2015). These repeats are translated in di-peptide repeat proteins which also spread like prions (Westergard et al, 2016). Intriguingly, C9orf72 was found to interact with cofilin-1 and to increase cofilin-1 phosphorylation through LIMK1/2 (Sivadasan et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Prion‐like protein aggregates exploit the RHO GTPase to cofilin‐1 signaling pathway to enter cells

et al. 2018

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Protein aggregation is a hallmark of diverse neurodegenerative diseases. Multiple lines of evidence have revealed that protein aggregates can penetrate inside cells and spread like prions. How such aggregates enter cells remains elusive. Through a focused siRNA screen targeting genes involved in membrane trafficking, we discovered that mutant SOD1 aggregates, like viruses, exploit cofilin-1 to remodel cortical actin and enter cells. Upstream of cofilin-1, signalling from the RHO GTPase and the ROCK1 and LIMK1 kinases controls cofilin-1 activity to remodel actin and modulate aggregate entry. In the spinal cord of symptomatic SOD1 transgenic mice, cofilin-1 phosphorylation is increased and actin dynamics altered. Importantly, the RHO to cofilin-1 signalling pathway also modulates entry of tau and α-synuclein aggregates. Our results identify a common host cell signalling pathway that diverse protein aggregates exploit to remodel actin and enter cells.

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Cell-to-Cell Transmission of Dipeptide Repeat Proteins Linked to C9orf72 -ALS/FTD

Cited by 174 publications

References 39 publications

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Prion‐like protein aggregates exploit the RHO GTPase to cofilin‐1 signaling pathway to enter cells

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