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

ABSTRACT: 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.

SUBMITTER: Gendron TF

PROVIDER: S-EPMC5576451 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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

Gendron Tania F TF Chew Jeannie J Stankowski Jeannette N JN Hayes Lindsey R LR Zhang Yong-Jie YJ Prudencio Mercedes M Carlomagno Yari Y Daughrity Lillian M LM Jansen-West Karen K Perkerson Emilie A EA O'Raw Aliesha A Cook Casey C Pregent Luc L Belzil Veronique V van Blitterswijk Marka M Tabassian Lilia J LJ Lee Chris W CW Yue Mei M Tong Jimei J Song Yuping Y Castanedes-Casey Monica M Rousseau Linda L Phillips Virginia V Dickson Dennis W DW Rademakers Rosa R Fryer John D JD Rush Beth K BK Pedraza Otto O Caputo Ana M AM Desaro Pamela P Palmucci Carla C Robertson Amelia A Heckman Michael G MG Diehl Nancy N NN Wiggs Edythe E Tierney Michael M Braun Laura L Farren Jennifer J Lacomis David D Ladha Shafeeq S Fournier Christina N CN McCluskey Leo F LF Elman Lauren B LB Toledo Jon B JB McBride Jennifer D JD Tiloca Cinzia C Morelli Claudia C Poletti Barbara B Solca Federica F Prelle Alessandro A Wuu Joanne J Jockel-Balsarotti Jennifer J Rigo Frank F Ambrose Christine C Datta Abhishek A Yang Weixing W Raitcheva Denitza D Antognetti Giovanna G McCampbell Alexander A Van Swieten John C JC Miller Bruce L BL Boxer Adam L AL Brown Robert H RH Bowser Robert R Miller Timothy M TM Trojanowski John Q JQ Grossman Murray M Berry James D JD Hu William T WT Ratti Antonia A Traynor Bryan J BJ Disney Matthew D MD Benatar Michael M Silani Vincenzo V Glass Jonathan D JD Floeter Mary Kay MK Rothstein Jeffrey D JD Boylan Kevin B KB Petrucelli Leonard L

Science translational medicine 20170301 383

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-associat ...[more]

PMID: 28356511

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Project description:Intronic expansion of the GGGGCC hexanucleotide repeat within the C9ORF72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis/motor neuron disease in both familial and sporadic cases. Initial reports indicate that this variant within the frontotemporal dementia/amyotrophic lateral sclerosis spectrum is associated with transactive response DNA binding protein (TDP-43) proteinopathy. The amyotrophic lateral sclerosis/motor neuron disease phenotype is not yet well characterized. We report the clinical and pathological phenotypes associated with pathogenic C9ORF72 mutations in a cohort of 563 cases from Northern England, including 63 with a family history of amyotrophic lateral sclerosis. One hundred and fifty-eight cases from the cohort (21 familial, 137 sporadic) were post-mortem brain and spinal cord donors. We screened DNA for the C9ORF72 mutation, reviewed clinical case histories and undertook pathological evaluation of brain and spinal cord. Control DNA samples (n = 361) from the same population were also screened. The C9ORF72 intronic expansion was present in 62 cases [11% of the cohort; 27/63 (43%) familial, 35/500 (7%) cases with sporadic amyotrophic lateral sclerosis/motor neuron disease]. Disease duration was significantly shorter in cases with C9ORF72-related amyotrophic lateral sclerosis (30.5 months) compared with non-C9ORF72 amyotrophic lateral sclerosis/motor neuron disease (36.3 months, P < 0.05). C9ORF72 cases included both limb and bulbar onset disease and all cases showed combined upper and lower motor neuron degeneration (amyotrophic lateral sclerosis). Thus, clinically, C9ORF72 cases show the features of a relatively rapidly progressive, but otherwise typical, variant of amyotrophic lateral sclerosis associated with both familial and sporadic presentations. Dementia was present in the patient or a close family member in 22/62 cases with C9ORF72 mutation (35%) based on diagnoses established from retrospective clinical case note review that may underestimate significant cognitive changes in late disease. All the C9ORF72 mutation cases showed classical amyotrophic lateral sclerosis pathology with TDP-43 inclusions in spinal motor neurons. Neuronal cytoplasmic inclusions and glial inclusions positive for p62 immunostaining in non-motor regions were strongly over-represented in the C9ORF72 cases. Extra-motor pathology in the frontal cortex (P < 0.0005) and the hippocampal CA4 subfield neurons (P < 0.0005) discriminated C9ORF72 cases strongly from the rest of the cohort. Inclusions in CA4 neurons were not present in non-C9ORF72 cases, indicating that this pathology predicts mutation status.

Dataset Information

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

Publications

Poly(GP) proteins are a useful pharmacodynamic marker for <i>C9ORF72</i>-associated amyotrophic lateral sclerosis.

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