Synaptic dysfunction induced by glycine-alanine dipeptides in C9orf72-ALS/FTD is rescued by SV2 replenishment.

Authors

• Brigid K Jensen
• Martin H Schuldi
• Kevin McAvoy
• Katelyn A Russell
• Ashley Boehringer
• Bridget M Curran
• Karthik Krishnamurthy
• Xinmei Wen
• Thomas Westergard
• Le Ma
• Aaron R Haeusler
• Dieter Edbauer
• Piera Pasinelli
• Davide Trotti

Publication/Presentation Date

5-8-2020

Abstract

The most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an intronic hexanucleotide repeat expansion in the C9orf72 gene. In disease, RNA transcripts containing this expanded region undergo repeat-associated non-AUG translation to produce dipeptide repeat proteins (DPRs), which are detected in brain and spinal cord of patients and are neurotoxic both in vitro and in vivo paradigms. We reveal here a novel pathogenic mechanism for the most abundantly detected DPR in ALS/FTD autopsy tissues, poly-glycine-alanine (GA). Previously, we showed motor dysfunction in a GA mouse model without loss of motor neurons. Here, we demonstrate that mobile GA aggregates are present within neurites, evoke a reduction in synaptic vesicle-associated protein 2 (SV2), and alter Ca

Volume

12

Issue

5

First Page

10722

Last Page

10722

ISSN

1757-4684

Published In/Presented At

Jensen, B. K., Schuldi, M. H., McAvoy, K., Russell, K. A., Boehringer, A., Curran, B. M., Krishnamurthy, K., Wen, X., Westergard, T., Ma, L., Haeusler, A. R., Edbauer, D., Pasinelli, P., & Trotti, D. (2020). Synaptic dysfunction induced by glycine-alanine dipeptides in C9orf72-ALS/FTD is rescued by SV2 replenishment. EMBO molecular medicine, 12(5), e10722. https://doi.org/10.15252/emmm.201910722

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

32347002

Department(s)

Administration and Leadership

Document Type

Article