Unconventional Translation of C9ORF72 GGGGCC Expansion Generates Insoluble Polypeptides Specific to c9FTD/ALS

Ash, Peter E.A.; Bieniek, Kevin F.; Gendron, Tania F.; Caulfield, Thomas R.; Lin, Wen Lang; DeJesus-Hernandez, Mariely; Blitterswijk, Marka van; Jansen-West, Karen; Paul, Joel R.; Rademakers, Rosa; Boylan, Kevin B.; Dickson, Dennis W.; Petrucelli, Leonard

doi:10.1016/j.neuron.2013.02.004

Cited by 1,001 publications

(1,031 citation statements)

References 20 publications

Supporting

Mentioning

995

Contrasting

Unclassified

Order By: Relevance

“…Repeat expansions in C9ORF72, called dipeptide repeat proteins, in patients with ALS are presumably generated by non-ATG translation, serve as a critical component of p62 positive inclusions found in the cerebellum and hippocampus, and can also be identified in CSF [44][45][46]. The specificity of dipeptide repeat proteins for these patients confers an opportunity for use in trials and could even be a therapeutic target [47].…”

Section: Toward Novel Outcome Measures and Biomarkers In Als Trialsmentioning

confidence: 99%

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

2015

View full text Add to dashboard Cite

The last 2 decades have seen a surge in the number of amyotrophic lateral sclerosis (ALS) clinical trials with the hope of finding successful treatments. Clinical trialists aim to repurpose existing drugs and test novel compounds to target potential ALS disease pathophysiology. Recent technological advancements have led to the discovery of new causative genetic agents and modes of delivering potential therapy, calling for increasingly sophisticated trial design. The standard ALS clinical trial design may be modified depending on study needs: type of therapy; route of therapy delivery; phase of therapy development; applicable subpopulation; market availability of therapy; and utility of telemedicine. Novel biomarkers of diagnostic, predictive, prognostic, and pharmacodynamic value are undergoing development and validation for use in clinical trials. Design modifications build on the traditional clinical trial design and may be employed in either the learning or confirming trial phase. Novel designs aim to minimize patient risk, study duration, and sample size, while improving efficiency and promoting statistical power to herald an exciting era for clinical research in ALS.

show abstract

Section: Toward Novel Outcome Measures and Biomarkers In Als Trialsmentioning

confidence: 99%

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

2015

View full text Add to dashboard Cite

show abstract

“…Potential pathomechanisms include the loss of function of normal C9orf72 protein, and/or toxicity resulting from the accumulation of G 4 C 2 transcripts that form RNA foci, interact with RNA‐binding proteins, and impair RNA processing 6. Expanded G 4 C 2 transcripts also lead to the production of five dipeptide repeat (DPR) proteins through repeat‐associated non‐ATG (RAN) translation 7, 8. RAN translation of sense transcripts of the repeat produces poly(GA), poly(GR), and poly(GP), while RAN translation of antisense repeat transcripts produces poly(PA), poly(PR), and poly(GP).…”

Section: Introductionmentioning

confidence: 99%

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

Meeter

Gendron

Sias

et al. 2018

Ann Clin Transl Neurol

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…The C9orf72 hexanucleotide G 4 C 2 repeat is located within the first intron of the locus, in a noncoding region, and yet is translated into polypeptides through a unique pathway known as repeat-associated non-AUG dependent (RAN) translation [130][131][132][133] (Fig. 1).…”

Section: Alternative Rna-based Mechanismsmentioning

confidence: 99%

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

Barmada

2015

Neurotherapeutics

View full text Add to dashboard Cite

The degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) inevitably causes paralysis and death within a matter of years. Mounting genetic and functional evidence suggest that abnormalities in RNA processing and metabolism underlie motor neuron loss in sporadic and familial ALS. Abnormal localization and aggregation of essential RNA-binding proteins are fundamental pathological features of sporadic ALS, and mutations in genes encoding RNA processing enzymes cause familial disease. Also, expansion mutations occurring in the noncoding region of C9orf72-the most common cause of inherited ALS-result in nuclear RNA foci, underscoring the link between abnormal RNA metabolism and neurodegeneration in ALS. This review summarizes the current understanding of RNA dysfunction in ALS, and builds upon this knowledge base to identify converging mechanisms of neurodegeneration in ALS. Potential targets for therapy development are highlighted, with particular emphasis on early and conserved pathways that lead to motor neuron loss in ALS.

show abstract

Unconventional Translation of C9ORF72 GGGGCC Expansion Generates Insoluble Polypeptides Specific to c9FTD/ALS

Cited by 1,001 publications

References 20 publications

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

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

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

Contact Info

Product

Resources

About