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Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36

Zachary T McEachin1, Tania F Gendron2, Nisha Raj3

  • 1Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Wallace H. Coulter Graduate Program in Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332, USA.

Neuron
|May 7, 2020
PubMed

Insights

Spinocerebellar ataxia type 36 (SCA36) and C9orf72-associated neurodegenerative diseases share repeat RNA translation into dipeptide repeat proteins (DPRs). However, SCA36 shows soluble poly(GP) without TDP-43 pathology, unlike C9orf72-ALS/FTD.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Hexanucleotide repeat expansions (HREs) in C9orf72 are a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
  • These HREs lead to the production of aggregating dipeptide repeat proteins (DPRs) through repeat-associated non-AUG (RAN) translation.
  • Intronic GGCCTG HREs cause spinocerebellar ataxia type 36 (SCA36).

Purpose of the Study:

  • To investigate whether GGCCTG HREs in SCA36 also undergo translation into DPRs.
  • To compare the types, abundance, and pathological characteristics of DPRs in SCA36 versus C9orf72-associated ALS/FTD (c9ALS/FTD).
  • To elucidate the mechanisms underlying divergent DPR pathology between these neurodegenerative diseases.

Main Methods:

  • Analysis of DPR production from GGCCTG HREs in SCA36 patient tissues.
  • Comparison of poly(GP) and poly(PR) abundance and translation mechanisms (canonical vs. RAN translation) between SCA36 and c9ALS/FTD.
  • Assessment of poly(GP) solubility and TDP-43 pathology in SCA36 patient tissue.
  • Investigation of chimeric DPR (cDPR) species in relation to divergent pathology.

Main Results:

  • GGCCTG HREs in SCA36 are translated into DPRs, including poly(GP) and poly(PR).
  • Poly(GP) is more abundant in SCA36 than c9ALS/FTD due to canonical AUG-mediated translation.
  • Poly(PR) frequency is comparable between SCA36 and c9ALS/FTD.
  • In SCA36, poly(GP) exists as a soluble species, and TDP-43 pathology is absent.
  • Aggregate-prone cDPR species contribute to the distinct DPR pathology observed in c9ALS/FTD and SCA36.

Conclusions:

  • SCA36 and c9ALS/FTD exhibit key differences in DPR translation, solubility, and aggregation.
  • Canonical translation of GGCCTG repeats in SCA36 leads to soluble poly(GP) and lacks TDP-43 pathology.
  • Divergent DPR pathology is linked to aggregate-prone cDPR species.

Keywords:
ALSC9orf72 expansionFTDRAN translationSCA36antisense oligonucleotide therapychimeric DPRsdipeptide repeatsneurodegeneration

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