Journal
EMBO JOURNAL
Volume 35, Issue 8, Pages 845-865Publisher
WILEY
DOI: 10.15252/embj.201592224
Keywords
amyotrophic lateral sclerosis; ERp57; PDIA1; protein disulfide isomerase
Categories
Funding
- Frick Foundation
- Muscular Dystrophy Association [382453]
- Millennium Institute [P09-015-F, CONICYT-USA2013-0003]
- Ring Initiative [ACT1109, ACT1114]
- FONDAP [15150012]
- FONDECYT [3110067, 1150743, 3130351, 11150579, 1150608, 1140549, 11090324, 1140301, 1130321, 1110433]
- Michael J Fox Foundation for Parkinson's Research
- COPEC-UC Foundation
- FONDEF [D11I1007]
- Office of Naval Research-Global (ONR-G) [N62909-16-1-2003]
- ALSRP Therapeutic Idea Award [AL150111]
- DRI-USA [2013-0030]
- Howard Hughes Medical Institute [HHMI INTNL 55005940]
- ALS Therapy Alliance
- NIH [NS057553-07]
- CONICYT Doctoral fellowship
- CONICYT [24110099]
- MINREB Millennium Nucleus Fund [RC120003]
- Pierre L. de Bourgknecht ALS Research Foundation
- Al-Athel ALS Research Foundation
- ALS Family Charitable Foundation
- NIH/NINDS [1R01NS050557]
- Alfonso Martin Escudero Foundation (Madrid)
- Biocenter Oulu, Finland
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Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) are ER foldases identified as possible ALS biomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized four ALS-linked mutations recently identified in two major PDI genes, PDIA1 and PDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of these PDI variants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutant PDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of these PDI mutants. Finally, targeting ERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifies ER proteostasis imbalance as a risk factor for ALS, driving initial stages of the disease.
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