Synaptic dysfunction induced by glycine‐alanine dipeptides in C9orf72‐ALS/FTD is rescued by SV2 replenishment
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 r...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2020-05-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201910722 |
| _version_ | 1797284081266851840 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Brigid K Jensen |
| collection | DOAJ |
| description | 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 Ca2+ influx and synaptic vesicle release. These phenotypes could be corrected by restoring SV2 levels. In GA mice, loss of SV2 was observed without reduction of motor neuron number. Notably, reduction in SV2 was seen in cortical and motor neurons derived from patient induced pluripotent stem cell lines, suggesting synaptic alterations also occur in patients. |
| first_indexed | 2024-03-07T17:42:42Z |
| format | Article |
| id | doaj.art-2b844e943b33490cb8b38258496834ea |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:42:42Z |
| publishDate | 2020-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-2b844e943b33490cb8b38258496834ea2024-03-02T15:39:02ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-05-01125n/an/a10.15252/emmm.201910722Synaptic dysfunction induced by glycine‐alanine dipeptides in C9orf72‐ALS/FTD is rescued by SV2 replenishmentBrigid K Jensen0Martin H Schuldi1Kevin McAvoy2Katelyn A Russell3Ashley Boehringer4Bridget M Curran5Karthik Krishnamurthy6Xinmei Wen7Thomas Westergard8Le Ma9Aaron R Haeusler10Dieter Edbauer11Piera Pasinelli12Davide Trotti13Jefferson Weinberg ALS Center Department of Neuroscience Vickie and Jack Farber Institute for Neuroscience Thomas Jefferson University Philadelphia PA USAGerman Center for Neurodegenerative Diseases (DZNE) Munich GermanyJefferson Weinberg ALS Center Department of Neuroscience Vickie and Jack Farber Institute for Neuroscience Thomas Jefferson University Philadelphia PA USAJefferson Weinberg ALS Center Department of Neuroscience Vickie and Jack Farber Institute for Neuroscience Thomas Jefferson University Philadelphia PA USAJefferson Weinberg ALS Center Department of Neuroscience Vickie and Jack Farber Institute for Neuroscience Thomas Jefferson University Philadelphia PA USADepartment of Neuroscience Vickie and Jack Farber Institute for Neuroscience Thomas Jefferson University Philadelphia PA USAJefferson Weinberg ALS Center Department of Neuroscience Vickie and Jack Farber Institute for Neuroscience Thomas Jefferson University Philadelphia PA USAJefferson Weinberg ALS Center Department of Neuroscience Vickie and Jack Farber Institute for Neuroscience Thomas Jefferson University Philadelphia PA USAJefferson Weinberg ALS Center Department of Neuroscience Vickie and Jack Farber Institute for Neuroscience Thomas Jefferson University Philadelphia PA USADepartment of Neuroscience Vickie and Jack Farber Institute for Neuroscience Thomas Jefferson University Philadelphia PA USAJefferson Weinberg ALS Center Department of Neuroscience Vickie and Jack Farber Institute for Neuroscience Thomas Jefferson University Philadelphia PA USAGerman Center for Neurodegenerative Diseases (DZNE) Munich GermanyJefferson Weinberg ALS Center Department of Neuroscience Vickie and Jack Farber Institute for Neuroscience Thomas Jefferson University Philadelphia PA USAJefferson Weinberg ALS Center Department of Neuroscience Vickie and Jack Farber Institute for Neuroscience Thomas Jefferson University Philadelphia PA USAAbstract 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 Ca2+ influx and synaptic vesicle release. These phenotypes could be corrected by restoring SV2 levels. In GA mice, loss of SV2 was observed without reduction of motor neuron number. Notably, reduction in SV2 was seen in cortical and motor neurons derived from patient induced pluripotent stem cell lines, suggesting synaptic alterations also occur in patients.https://doi.org/10.15252/emmm.201910722amyotrophic lateral sclerosisC9orf72dipeptide repeat proteinsmotor deficitsynaptic transmission |
| spellingShingle | 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 Synaptic dysfunction induced by glycine‐alanine dipeptides in C9orf72‐ALS/FTD is rescued by SV2 replenishment EMBO Molecular Medicine amyotrophic lateral sclerosis C9orf72 dipeptide repeat proteins motor deficit synaptic transmission |
| title | Synaptic dysfunction induced by glycine‐alanine dipeptides in C9orf72‐ALS/FTD is rescued by SV2 replenishment |
| title_full | Synaptic dysfunction induced by glycine‐alanine dipeptides in C9orf72‐ALS/FTD is rescued by SV2 replenishment |
| title_fullStr | Synaptic dysfunction induced by glycine‐alanine dipeptides in C9orf72‐ALS/FTD is rescued by SV2 replenishment |
| title_full_unstemmed | Synaptic dysfunction induced by glycine‐alanine dipeptides in C9orf72‐ALS/FTD is rescued by SV2 replenishment |
| title_short | Synaptic dysfunction induced by glycine‐alanine dipeptides in C9orf72‐ALS/FTD is rescued by SV2 replenishment |
| title_sort | synaptic dysfunction induced by glycine alanine dipeptides in c9orf72 als ftd is rescued by sv2 replenishment |
| topic | amyotrophic lateral sclerosis C9orf72 dipeptide repeat proteins motor deficit synaptic transmission |
| url | https://doi.org/10.15252/emmm.201910722 |
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