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.
Keywords: ALS; AMPA; Amyotrophic lateral sclerosis; C9orf72; DPP6; ELP3; ER; Excitotoxicity; FUS/TLS; GFAP; IP(3); ITPR2; Motor neuron disease; Neurogenetics; Nuclear shrinkage; PBS; PCR; PFN1; PLCD1; POAG; Phospholipase C delta 1; SDS-PAGE; SNP; SOD1; SOD1-G93A mice; TAR-DNA binding protein 43; TARDBP; UBQLN2; UNC13a; amyotrophic lateral sclerosis; chromosome 9 open reading frame 72; dipeptidyl-peptidase 6; elongator protein 3; endoplasmic reticulum; fused in sarcoma/translocated in liposarcoma; glial fibrillary acidic protein; inositol 1,4,5-trisphosphate; inositol 1,4,5-trisphosphate receptor 2; phosphate buffered saline; phosphoinositide phospholipase C; polymerase chain reaction; primary open-angle glaucoma; profilin 1; single nucleotide polymorphism; sodium dodecyl sulfate polyacrylamide gel electrophoresis; superoxide dismutase 1; ubiquilin 2; unc-13 homolog A; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.
© 2013.