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Genetic ablation of phospholipase C delta 1 increases survival in SOD1(G93A) mice.
Neurobiol Dis. 2013 Dec; 60:11-7.ND

Abstract

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 (PLCδ1), to investigate its role in ALS. PLCδ1 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 PLCδ1 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 PLCδ1. Interestingly, genetic ablation of PLCδ1 prevents nuclear shrinkage of motor neurons in ALS mice at end stage. These results indicate that PLCD1 contributes to ALS and that PLCδ1 may be a new target for future studies.

Authors+Show Affiliations

Laboratory of Neurobiology, Belgium; Leuven Research Institute of Neuroscience and Disease (LIND), KU Leuven, Belgium; Vesalius Research Center, VIB, Belgium. Electronic address: kim.staats@vib-kuleuven.be.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23969236

Citation

Staats, Kim A., et al. "Genetic Ablation of Phospholipase C Delta 1 Increases Survival in SOD1(G93A) Mice." Neurobiology of Disease, vol. 60, 2013, pp. 11-7.
Staats KA, Van Helleputte L, Jones AR, et al. Genetic ablation of phospholipase C delta 1 increases survival in SOD1(G93A) mice. Neurobiol Dis. 2013;60:11-7.
Staats, K. A., Van Helleputte, L., Jones, A. R., Bento-Abreu, A., Van Hoecke, A., Shatunov, A., Simpson, C. L., Lemmens, R., Jaspers, T., Fukami, K., Nakamura, Y., Brown, R. H., Van Damme, P., Liston, A., Robberecht, W., Al-Chalabi, A., & Van Den Bosch, L. (2013). Genetic ablation of phospholipase C delta 1 increases survival in SOD1(G93A) mice. Neurobiology of Disease, 60, 11-7. https://doi.org/10.1016/j.nbd.2013.08.006
Staats KA, et al. Genetic Ablation of Phospholipase C Delta 1 Increases Survival in SOD1(G93A) Mice. Neurobiol Dis. 2013;60:11-7. PubMed PMID: 23969236.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genetic ablation of phospholipase C delta 1 increases survival in SOD1(G93A) mice. AU - Staats,Kim A, AU - Van Helleputte,Lawrence, AU - Jones,Ashley R, AU - Bento-Abreu,André, AU - Van Hoecke,Annelies, AU - Shatunov,Aleksey, AU - Simpson,Claire L, AU - Lemmens,Robin, AU - Jaspers,Tom, AU - Fukami,Kiyoko, AU - Nakamura,Yoshikazu, AU - Brown,Robert H,Jr AU - Van Damme,Philip, AU - Liston,Adrian, AU - Robberecht,Wim, AU - Al-Chalabi,Ammar, AU - Van Den Bosch,Ludo, Y1 - 2013/08/19/ PY - 2013/06/13/received PY - 2013/07/31/revised PY - 2013/08/07/accepted PY - 2013/8/24/entrez PY - 2013/8/24/pubmed PY - 2014/6/16/medline KW - ALS KW - AMPA KW - Amyotrophic lateral sclerosis KW - C9orf72 KW - DPP6 KW - ELP3 KW - ER KW - Excitotoxicity KW - FUS/TLS KW - GFAP KW - IP(3) KW - ITPR2 KW - Motor neuron disease KW - Neurogenetics KW - Nuclear shrinkage KW - PBS KW - PCR KW - PFN1 KW - PLCD1 KW - POAG KW - Phospholipase C delta 1 KW - SDS-PAGE KW - SNP KW - SOD1 KW - SOD1-G93A mice KW - TAR-DNA binding protein 43 KW - TARDBP KW - UBQLN2 KW - UNC13a KW - amyotrophic lateral sclerosis KW - chromosome 9 open reading frame 72 KW - dipeptidyl-peptidase 6 KW - elongator protein 3 KW - endoplasmic reticulum KW - fused in sarcoma/translocated in liposarcoma KW - glial fibrillary acidic protein KW - inositol 1,4,5-trisphosphate KW - inositol 1,4,5-trisphosphate receptor 2 KW - phosphate buffered saline KW - phosphoinositide phospholipase C KW - polymerase chain reaction KW - primary open-angle glaucoma KW - profilin 1 KW - single nucleotide polymorphism KW - sodium dodecyl sulfate polyacrylamide gel electrophoresis KW - superoxide dismutase 1 KW - ubiquilin 2 KW - unc-13 homolog A KW - α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid SP - 11 EP - 7 JF - Neurobiology of disease JO - Neurobiol Dis VL - 60 N2 - 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 (PLCδ1), to investigate its role in ALS. PLCδ1 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 PLCδ1 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 PLCδ1. Interestingly, genetic ablation of PLCδ1 prevents nuclear shrinkage of motor neurons in ALS mice at end stage. These results indicate that PLCD1 contributes to ALS and that PLCδ1 may be a new target for future studies. SN - 1095-953X UR - https://www.unboundmedicine.com/medline/citation/23969236/Genetic_ablation_of_phospholipase_C_delta_1_increases_survival_in_SOD1_G93A__mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(13)00227-1 DB - PRIME DP - Unbound Medicine ER -