Prevalence of brain and spinal cord inclusions, including dipeptide repeat proteins, in patients with the <scp>C</scp>9<scp>ORF</scp>72 hexanucleotide repeat expansion: a systematic neuropathological review

Schipper, Luuk J.; Raaphorst, Joost; Aronica, Eleonora; Baas, Frank; Haan, R. den; Visser, Marjolein; Troost, Dirk

doi:10.1111/nan.12284

Cited by 34 publications

(32 citation statements)

References 73 publications

(51 reference statements)

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“…A tremendous amount of effort has gone into defining several nonmutually exclusive disease mechanisms suggested by this mutation (Haeusler et al 2016;Taylor et al 2016), yet the relative contributions of each mutation are unclear in vivo. C9 ALS/FTD is similar to most other forms of ALS in that it is marked by TDP-43 pathology but also has a distinct class of Ub + /p62 + cytoplasmic inclusions containing dipeptide repeat (DPR) proteins made by RAN translation (Kearse and Todd 2014;Schipper et al 2016). Why C9 causes some people to get pure ALS or FTD or a mixture of both is a mystery.…”

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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“…C9-RAN-T DPRs are key pathogenic mediators of C9orf72-linked ALS/FTD (Gitler and Tsuiji, 2016). In patients, DPRs have been reported throughout the CNS, including the spinal cord, frontal cortex, motor cortex, hippocampus, and cerebellum (Schipper et al, 2015). Recent studies showed toxicity and cellular dysfunctions resulting from some of these DPRs, however their ability to transmit between cells has yet to be described.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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SUMMARY Aberrant hexanucleotide repeat expansions in C9orf72 are the most common genetic change underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). RNA transcripts containing these expansions undergo repeat associated non-ATG (RAN) translation to form five dipeptide repeat proteins (DPRs). DPRs are found as aggregates throughout the CNS of C9orf72-ALS/FTD patients and some cause degeneration when expressed in vitro in neuronal cultures and in vivo in animal models. The spread of characteristic disease-related proteins drives the progression of pathology in many neurodegenerative diseases. While DPR toxic mechanisms continue to be investigated, the potential for DPRs to spread has yet to be determined. Utilizing different experimental cell culture platforms, including spinal motor neurons derived from induced pluripotent stem cells from C9orf72-ALS patients, we found evidence for cell-to-cell spreading of DPRs via exosome-dependent and independent pathways, which may potentially be relevant to disease.

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“…2) (Ash et al 2013;Gendron et al 2013;Mann et al 2013;Mori et al 2013a,c;Zu et al 2013). Immunohistochemical analyses using multiple antibodies against the various DPR proteins have demonstrated highly specific staining of cytoplasmic inclusions, nuclear inclusions, or dystrophic neurites in c9ALS/FTD patients (Ash et al 2013;Gendron et al 2013;Mackenzie et al 2013Mackenzie et al , 2015Mann et al 2013;Mori et al 2013a,c;Zu et al 2013;Zhang et al 2014;Schipper et al 2015;Schludi et al 2015). These inclusions, which are present in neurons throughout the CNS (Ash et al 2013;Mackenzie et al 2013) and in ependymal cells of the spinal cord central canal and lateral ventricles (Schludi et al 2015), can contain multiple DPR proteins (Mori et al 2013a), are positive for p62 (Mann et al 2013;Mori et al 2013a), and, at least in the case of poly(GA) inclusions, contain filaments (Zhang et al 2014).…”

Section: Ran Translation Dpr Protein Pathology: a Neuropathological Hmentioning

confidence: 99%

Disease Mechanisms ofC9ORF72Repeat Expansions

Gendron

Petrucelli

2017

Cold Spring Harb Perspect Med

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GC repeat expansions within the gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These bidirectionally transcribed expansions lead to (1) the accumulation of sense GC and antisense GC repeat-containing RNA, (2) the production of proteins of repeating dipeptides through unconventional translation of these transcripts, and (3) decreased mRNA and protein expression. Consequently, there is ample opportunity for the mutation to give rise to a spectrum of clinical manifestations, ranging from muscle weakness and atrophy to changes in behavior and cognition. It is thus somewhat surprising that investigations of these three seemingly disparate events often converge on similar putative pathological mechanisms. This review aims to summarize the findings and questions emerging from the field's quest to decipher how repeat expansions cause the devastating diseases collectively referred to as "c9ALS/FTD."

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Prevalence of brain and spinal cord inclusions, including dipeptide repeat proteins, in patients with the C9ORF72 hexanucleotide repeat expansion: a systematic neuropathological review

Cited by 34 publications

References 73 publications

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

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

Disease Mechanisms ofC9ORF72Repeat Expansions

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