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PLoS One. 2016 Oct 24;11(10):e0165084. doi: 10.1371/journal.pone.0165084. eCollection 2016.

Distinct C9orf72-Associated Dipeptide Repeat Structures Correlate with Neuronal Toxicity.

Author information

1
Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, Michigan, United States of America.
2
Department of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America.
3
UCLA-DOE Institute for Genomics and Proteomics, University of California, Los Angeles, California, United States of America.
4
Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan, United States of America.
5
Veterans Affairs Medical Center, Ann Arbor, Michigan, United States of America.
6
Biophysics Program, University of Michigan, Ann Arbor, Michigan, United States of America.

Abstract

Hexanucleotide repeat expansions in C9orf72 are the most common inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansions elicit toxicity in part through repeat-associated non-AUG (RAN) translation of the intronic (GGGGCC)n sequence into dipeptide repeat-containing proteins (DPRs). Little is known, however, about the structural characteristics and aggregation propensities of the dipeptide units comprising DPRs. To address this question, we synthesized dipeptide units corresponding to the three sense-strand RAN translation products, analyzed their structures by circular dichroism, electron microscopy and dye binding assays, and assessed their relative toxicity when applied to primary cortical neurons. Short, glycine-arginine (GR)3 dipeptides formed spherical aggregates and selectively reduced neuronal survival compared to glycine-alanine (GA)3 and glycine-proline (GP)3 dipeptides. Doubling peptide length had little effect on the structure of GR or GP peptides, but (GA)6 peptides formed β-sheet rich aggregates that bound thioflavin T and Congo red yet lacked the typical fibrillar morphology of amyloids. Aging of (GA)6 dipeptides increased their β-sheet content and enhanced their toxicity when applied to neurons. We also observed that the relative toxicity of each tested dipeptide was proportional to peptide internalization. Our results demonstrate that different C9orf72-related dipeptides exhibit distinct structural properties that correlate with their relative toxicity.

PMID:
27776165
PMCID:
PMC5077081
DOI:
10.1371/journal.pone.0165084
[Indexed for MEDLINE]
Free PMC Article

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