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Repeated repeat problems: Combinatorial effect of C9orf72-derived dipeptide repeat proteins.

April L Darling1, Leonid Breydo1, Emma G Rivas1

  • 1Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33612, USA.

International Journal of Biological Macromolecules
|January 15, 2019
PubMed
Summary
This summary is machine-generated.

The most common genetic cause of ALS and FTD, C9orf72 expansion mutations, produce dipeptide repeat proteins (DPRs). Combined expression of different DPRs creates unique cellular outcomes, unlike single DPR expression, indicating complex disease interactions.

Keywords:
ALSC9orf72Dipeptide repeat proteinFTDIntrinsically disordered proteinsPoly(GA)Poly(PR)

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Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • C9orf72 gene expansions are the leading genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).
  • These expansions result in C9orf72 loss of function, RNA foci, and the production of five distinct dipeptide repeat proteins (DPRs) via non-AUG translation.
  • Limited understanding exists regarding the interactions between different DPR species within a single cell.

Purpose of the Study:

  • To investigate the cellular consequences and structural differences arising from the combined expression of various C9orf72-derived DPR species.
  • To explore the potential interplay between distinct DPR variants when co-expressed within cells.

Main Methods:

  • Experimental co-expression of different C9orf72-derived dipeptide repeat proteins (e.g., poly(GA), poly(GP), poly(GR), poly(PA), poly(PR)) in cellular models.
  • Analysis of cellular outcomes and structural alterations resulting from single versus combined DPR expression.

Main Results:

  • The simultaneous expression of distinct DPR species leads to cellular outcomes and structural changes distinct from those observed with single DPR expression.
  • These findings suggest complex biological interactions occur when multiple DPR variants are present concurrently.

Conclusions:

  • Combined expression of different C9orf72-derived DPRs results in unique cellular phenotypes.
  • Further research is crucial to elucidate how the co-expression of multiple DPRs influences disease progression in ALS and FTD.