Open AccessSynaptic dysfunction induced by glycine‐alanine dipeptides in C9orf72‐ ALS / FTD is rescued by SV 2 replenishment
Author(s) -
Jensen Brigid K,
Schuldi Martin H,
McAvoy Kevin,
Russell Katelyn A,
Boehringer Ashley,
Curran Bridget M,
Krishnamurthy Karthik,
Wen Xinmei,
Westergard Thomas,
Ma Le,
Haeusler Aaron R,
Edbauer Dieter,
Pasinelli Piera,
Trotti Davide
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201910722
Subject(s) - c9orf72 , amyotrophic lateral sclerosis , neurite , motor neuron , synaptic vesicle , neurodegeneration , microbiology and biotechnology , trinucleotide repeat expansion , biology , synapse , synapsin i , neuroscience , chemistry , biochemistry , spinal cord , medicine , in vitro , gene , pathology , vesicle , allele , disease , membrane
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 ( DPR s), 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 ( SV 2), and alter Ca 2+ influx and synaptic vesicle release. These phenotypes could be corrected by restoring SV 2 levels. In GA mice, loss of SV 2 was observed without reduction of motor neuron number. Notably, reduction in SV 2 was seen in cortical and motor neurons derived from patient induced pluripotent stem cell lines, suggesting synaptic alterations also occur in patients.