Timing and significance of pathological features in<i>C9orf72</i>expansion-associated frontotemporal dementia

Vatsavayai, Sarat C.; Yoon, Soo Jin; Gardner, Raquel C.; Gendron, Tania F.; Vargas, Jose Norberto S.; Trujillo, Andrew; Pribadi, Mochtar; Phillips, Joanna J.; Gaus, Stephanie E.; Hixson, John D.; Garcia, Paul A.; Rabinovici, Gil D.; Coppola, Giovanni; Geschwind, Daniel H.; Petrucelli, Leonard; Miller, Bruce L.; Seeley, William W.

doi:10.1093/brain/aww250

Cited by 149 publications

(150 citation statements)

References 43 publications

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“…Our observation that CSF poly(GP) is detected in asymptomatic C9ORF72 mutation carriers is consistent with the emergence of brain c9RAN protein pathology before symptom onset (24). It also suggests that the primary source of poly(GP) in CSF is not the release of this protein from dying cells but rather its secretion from living cells.…”

Section: Discussionsupporting

confidence: 83%

Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72 -associated amyotrophic lateral sclerosis

et al. 2017

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There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNA–mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA–based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.

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Section: Discussionsupporting

confidence: 83%

Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72 -associated amyotrophic lateral sclerosis

et al. 2017

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“…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. These studies provide converging evidence that poly(GP) expression arises early in the lifespan of C9orf72 expansion carriers.…”

Section: Discussionmentioning

confidence: 78%

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

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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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“…Whether this is the case for other human diseases exhibiting TDP-43 pathology, such as ALS/FTD or sporadic inclusion body myopathy, remains to be seen. Interestingly, one illuminating patient, a 74-year-old female with frontotemporal dementia due to C9orf72 repeat expansion who underwent temporal lobe resection for epilepsy 5 years prior to her first frontotemporal dementia symptom was reported recently [28]. Archival surgical resection tissue demonstrated RNA foci, dipeptide repeat protein inclusions, and loss of nuclear TDP-43 but without TDP-43 inclusions despite florid TDP-43 inclusions at autopsy 8 years after first symptoms, raising important questions about the timing and significance of TDP-43-associated events.…”

Section: Discussionmentioning

confidence: 99%

Cryptic exon incorporation occurs in Alzheimer’s brain lacking TDP-43 inclusion but exhibiting nuclear clearance of TDP-43

et al. 2017

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Abnormal accumulation of TDP-43 into cytoplasmic or nuclear inclusions with accompanying nuclear clearance, a common pathology initially identified in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), has also been found in Alzheimer’ disease (AD). TDP-43 serves as a splicing repressor of nonconserved cryptic exons and that such function is compromised in brains of ALS and FTD patients, suggesting that nuclear clearance of TDP-43 underlies its inability to repress cryptic exons. However, whether TDP-43 cytoplasmic aggregates are a prerequisite for the incorporation of cryptic exons is not known. Here, we assessed hippocampal tissues from 34 human postmortem brains including cases with confirmed diagnosis of AD neuropathologic changes along with age-matched controls. We found that cryptic exon incorporation occurred in all AD cases exhibiting TDP-43 pathology. Furthermore, incorporation of cryptic exons was observed in the hippocampus when TDP-43 inclusions was restricted only to the amygdala, the earliest stage of TDP-43 progression. Importantly, cryptic exon incorporation could be detected in AD brains lacking TDP-43 inclusion but exhibiting nuclear clearance of TDP-43. These data support the notion that the functional consequence of nuclear depletion of TDP-43 as determined by cryptic exon incorporation likely occurs as an early event of TDP-43 proteinopathy and may have greater contribution to the pathogenesis of AD than currently appreciated. Early detection and effective repression of cryptic exons in AD patients may offer important diagnostic and therapeutic implications for this devastating illness of the elderly.

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Timing and significance of pathological features inC9orf72expansion-associated frontotemporal dementia

Cited by 149 publications

References 43 publications

Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72 -associated amyotrophic lateral sclerosis

Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72 -associated amyotrophic lateral sclerosis

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

Cryptic exon incorporation occurs in Alzheimer’s brain lacking TDP-43 inclusion but exhibiting nuclear clearance of TDP-43

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