Genetic ablation of phospholipase C delta 1 increases survival in SOD1(G93A) mice

Kim A Staats; Lawrence Van Helleputte; Ashley R Jones; André Bento-Abreu; Annelies Van Hoecke; Aleksey Shatunov; Claire L Simpson; Robin Lemmens; Tom Jaspers; Kiyoko Fukami; Yoshikazu Nakamura; Robert H Brown; Philip Van Damme; Adrian Liston; Wim Robberecht; Ammar Al-Chalabi; Ludo Van Den Bosch

doi:10.1016/j.nbd.2013.08.006

Genetic ablation of phospholipase C delta 1 increases survival in SOD1(G93A) mice

Kim A Staats, Lawrence Van Helleputte, Ashley R Jones, André Bento-Abreu, Annelies Van Hoecke, Aleksey Shatunov, Claire L Simpson, Robin Lemmens, Tom Jaspers, Kiyoko Fukami, Yoshikazu Nakamura, Robert H Brown, Philip Van Damme, Adrian Liston, Wim Robberecht, Ammar Al-Chalabi, Ludo Van Den Bosch

KU Leuven

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

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.

Original language	English
Article number	N/A
Pages (from-to)	11-17
Number of pages	7
Journal	Neurobiology of Disease
Volume	60
Issue number	N/A
DOIs	https://doi.org/10.1016/j.nbd.2013.08.006
Publication status	Published - Dec 2013

Keywords

Amyotrophic lateral sclerosis
Phospholipase C delta 1
Neurogenetics
SOD1-G93A mice
Excitotoxicity
Motor neuron disease
Nuclear shrinkage
AMYOTROPHIC-LATERAL-SCLEROSIS
GENOME-WIDE ASSOCIATION
MOTOR-NEURON DEGENERATION
TRANSGENIC MOUSE MODEL
HEXANUCLEOTIDE REPEAT
MUTATIONS
SUSCEPTIBILITY
DISEASE
C-DELTA-1
ALS
Acknowledged-BRC
Acknowledged-BRC-13/14

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10.1016/j.nbd.2013.08.006

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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(N/A), 11-17. Article N/A. https://doi.org/10.1016/j.nbd.2013.08.006

@article{b521a493c406410381c822373c132067,

title = "Genetic ablation of phospholipase C delta 1 increases survival in SOD1(G93A) mice",

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.",

keywords = "Amyotrophic lateral sclerosis, Phospholipase C delta 1, Neurogenetics, SOD1-G93A mice, Excitotoxicity, Motor neuron disease, Nuclear shrinkage, AMYOTROPHIC-LATERAL-SCLEROSIS, GENOME-WIDE ASSOCIATION, MOTOR-NEURON DEGENERATION, TRANSGENIC MOUSE MODEL, HEXANUCLEOTIDE REPEAT, MUTATIONS, SUSCEPTIBILITY, DISEASE, C-DELTA-1, ALS, Acknowledged-BRC, Acknowledged-BRC-13/14",

author = "Staats, {Kim A} and {Van Helleputte}, Lawrence and Jones, {Ashley R} and Andr{\'e} Bento-Abreu and {Van Hoecke}, Annelies and Aleksey Shatunov and Simpson, {Claire L} and Robin Lemmens and Tom Jaspers and Kiyoko Fukami and Yoshikazu Nakamura and Brown, {Robert H} and {Van Damme}, Philip and Adrian Liston and Wim Robberecht and Ammar Al-Chalabi and {Van Den Bosch}, Ludo",

year = "2013",

month = dec,

doi = "10.1016/j.nbd.2013.08.006",

language = "English",

volume = "60",

pages = "11--17",

journal = "Neurobiology of Disease",

issn = "0969-9961",

publisher = "Elsevier",

number = "N/A",

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Staats, KA, Van Helleputte, L, Jones, AR, Bento-Abreu, A, Van Hoecke, A, Shatunov, A, Simpson, CL, Lemmens, R, Jaspers, T, Fukami, K, Nakamura, Y, Brown, RH, 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, vol. 60, no. N/A, N/A, pp. 11-17. https://doi.org/10.1016/j.nbd.2013.08.006

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

AU - Van Damme, Philip

AU - Liston, Adrian

AU - Robberecht, Wim

AU - Al-Chalabi, Ammar

AU - Van Den Bosch, Ludo

PY - 2013/12

Y1 - 2013/12

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.

AB - 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.

KW - Amyotrophic lateral sclerosis

KW - Phospholipase C delta 1

KW - Neurogenetics

KW - SOD1-G93A mice

KW - Excitotoxicity

KW - Motor neuron disease

KW - Nuclear shrinkage

KW - AMYOTROPHIC-LATERAL-SCLEROSIS

KW - GENOME-WIDE ASSOCIATION

KW - MOTOR-NEURON DEGENERATION

KW - TRANSGENIC MOUSE MODEL

KW - HEXANUCLEOTIDE REPEAT

KW - MUTATIONS

KW - SUSCEPTIBILITY

KW - DISEASE

KW - C-DELTA-1

KW - ALS

KW - Acknowledged-BRC

KW - Acknowledged-BRC-13/14

U2 - 10.1016/j.nbd.2013.08.006

DO - 10.1016/j.nbd.2013.08.006

M3 - Article

C2 - 23969236

SN - 0969-9961

VL - 60

SP - 11

EP - 17

JO - Neurobiology of Disease

JF - Neurobiology of Disease

IS - N/A

M1 - N/A

ER -

Genetic ablation of phospholipase C delta 1 increases survival in SOD1(G93A) mice

Abstract

Keywords

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