Journal
NEUROBIOLOGY OF DISEASE
Volume 60, Issue -, Pages 11-17Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2013.08.006
Keywords
Amyotrophic lateral sclerosis; Phospholipase C delta 1; Neurogenetics; SOD1-G93A mice; Excitotoxicity; Motor neuron disease; Nuclear shrinkage
Categories
Funding
- ALS Association
- Motor Neurone Disease Association of England, Wales and Northern Ireland
- NIHR Dementia Biomedical Research Unit at South London
- Maudsley NHS Foundation Trust
- King's College London
- Fund for Scientific Research Flanders (FWO-Vlaanderen)
- University of Leuven (KU Leuven)
- Belgian Government (Interuniversity Attraction Poles, programme of the Belgian Federal Science Policy Office) [P7/16]
- ALS Therapy Alliance
- Angel Fund
- European Community [259867]
- National Human Genome Research Institute, National Institutes of Health
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Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease, resulting in selective motor neuron degeneration and paralysis. Patients die approximately 3-5 years after diagnosis. Disease pathophysiology is multifactorial, including excitotoxicity, but is not yet fully understood. Genetic analysis has proven fruitful in the past to further understand genes modulating the disease and increase knowledge of disease mechanisms. Here, we revisit a previously performed microsatellite analysis in ALS and focus on another hit, PLCD1, encoding phospholipase C delta 1 (PLC delta 1), to investigate its role in ALS. PLC delta 1 may contribute to excitotoxicity as it increases inositol 1,4,5-trisphosphate (IP3) formation, which releases calcium from the endoplasmic reticulum through IP3 receptors. We find that expression of PLC delta 1 is increased in ALS mouse spinal cord and in neurons from ALS mice. Furthermore, genetic ablation of this protein in ALS mice significantly increases survival, but does not affect astrogliosis, microgliosis, aggregation or the amount of motor neurons at end stage compared to ALS mice with PLC delta 1. Interestingly, genetic ablation of PLC delta 1 prevents nuclear shrinkage of motor neurons in ALS mice at end stage. These results indicate that PLCD1 contributes to ALS and that PLC delta 1 may be a new target for future studies. (C) 2013 Elsevier Inc. All rights reserved.
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