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Increased surface P2X4 receptors by mutant SOD1 proteins contribute to ALS pathogenesis in SOD1-G93A mice

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Increased surface P2X4 receptors by mutant SOD1 proteins contribute to ALS pathogenesis in SOD1-G93A mice. / Bertin, Eléonore; Martinez, Audrey; Fayoux, Anne; Carvalho, Kevin; Carracedo, Sara; Fernagut, Pierre-Olivier; Koch-Nolte, Friedrich; Blum, David; Bertrand, Sandrine S; Boué-Grabot, Eric.

In: CELL MOL LIFE SCI, Vol. 79, No. 8, 431, 19.07.2022.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Bertin, E, Martinez, A, Fayoux, A, Carvalho, K, Carracedo, S, Fernagut, P-O, Koch-Nolte, F, Blum, D, Bertrand, SS & Boué-Grabot, E 2022, 'Increased surface P2X4 receptors by mutant SOD1 proteins contribute to ALS pathogenesis in SOD1-G93A mice', CELL MOL LIFE SCI, vol. 79, no. 8, 431. https://doi.org/10.1007/s00018-022-04461-5

APA

Bertin, E., Martinez, A., Fayoux, A., Carvalho, K., Carracedo, S., Fernagut, P-O., Koch-Nolte, F., Blum, D., Bertrand, S. S., & Boué-Grabot, E. (2022). Increased surface P2X4 receptors by mutant SOD1 proteins contribute to ALS pathogenesis in SOD1-G93A mice. CELL MOL LIFE SCI, 79(8), [431]. https://doi.org/10.1007/s00018-022-04461-5

Vancouver

Bertin E, Martinez A, Fayoux A, Carvalho K, Carracedo S, Fernagut P-O et al. Increased surface P2X4 receptors by mutant SOD1 proteins contribute to ALS pathogenesis in SOD1-G93A mice. CELL MOL LIFE SCI. 2022 Jul 19;79(8). 431. https://doi.org/10.1007/s00018-022-04461-5

Bibtex

@article{2238cb7aec754b6abb3c30765661309a,
title = "Increased surface P2X4 receptors by mutant SOD1 proteins contribute to ALS pathogenesis in SOD1-G93A mice",
abstract = "Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron (MN) disease characterized by protein misfolding and aggregation leading to cellular degeneration. So far neither biomarker, nor effective treatment has been found. ATP signaling and P2X4 receptors (P2X4) are upregulated in various neurodegenerative diseases. Here we show that several ALS-related misfolded proteins including mutants of SOD1 or TDP-43 lead to a significant increase in surface P2X4 receptor density and function in vitro. In addition, we demonstrate in the spinal the cord of SOD1-G93A (SOD1) mice that misfolded SOD1-G93A proteins directly interact with endocytic adaptor protein-2 (AP2); thus, acting as negative competitors for the interaction between AP2 and P2X4, impairing constitutive P2X4 endocytosis. The higher P2X4 surface density was particularly observed in peripheral macrophages of SOD1 mice before the onset and during the progression of ALS symptoms positioning P2X4 as a potential early biomarker for ALS. P2X4 expression was also upregulated in spinal microglia of SOD1 mice during ALS and affect microglial inflammatory responses. Importantly, we report using double transgenic SOD1 mice expressing internalization-defective P2X4mCherryIN knock-in gene or invalidated for the P2X4 gene that P2X4 is instrumental for motor symptoms, ALS progression and survival. This study highlights the role of P2X4 in the pathophysiology of ALS and thus its potential for the development of biomarkers and treatments. We also decipher the molecular mechanism by which misfolded proteins related to ALS impact P2X4 trafficking at early pathological stage in cells expressing-P2X4.",
keywords = "Amyotrophic Lateral Sclerosis/genetics, Animals, Disease Models, Animal, Disease Progression, Mice, Mice, Transgenic, Motor Neuron Disease/genetics, Motor Neurons/metabolism, Receptors, Purinergic P2X4/genetics, Spinal Cord/metabolism, Superoxide Dismutase-1/genetics",
author = "El{\'e}onore Bertin and Audrey Martinez and Anne Fayoux and Kevin Carvalho and Sara Carracedo and Pierre-Olivier Fernagut and Friedrich Koch-Nolte and David Blum and Bertrand, {Sandrine S} and Eric Bou{\'e}-Grabot",
note = "{\textcopyright} 2022. The Author(s).",
year = "2022",
month = jul,
day = "19",
doi = "10.1007/s00018-022-04461-5",
language = "English",
volume = "79",
journal = "CELL MOL LIFE SCI",
issn = "1420-682X",
publisher = "Birkhauser Verlag Basel",
number = "8",

}

RIS

TY - JOUR

T1 - Increased surface P2X4 receptors by mutant SOD1 proteins contribute to ALS pathogenesis in SOD1-G93A mice

AU - Bertin, Eléonore

AU - Martinez, Audrey

AU - Fayoux, Anne

AU - Carvalho, Kevin

AU - Carracedo, Sara

AU - Fernagut, Pierre-Olivier

AU - Koch-Nolte, Friedrich

AU - Blum, David

AU - Bertrand, Sandrine S

AU - Boué-Grabot, Eric

N1 - © 2022. The Author(s).

PY - 2022/7/19

Y1 - 2022/7/19

N2 - Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron (MN) disease characterized by protein misfolding and aggregation leading to cellular degeneration. So far neither biomarker, nor effective treatment has been found. ATP signaling and P2X4 receptors (P2X4) are upregulated in various neurodegenerative diseases. Here we show that several ALS-related misfolded proteins including mutants of SOD1 or TDP-43 lead to a significant increase in surface P2X4 receptor density and function in vitro. In addition, we demonstrate in the spinal the cord of SOD1-G93A (SOD1) mice that misfolded SOD1-G93A proteins directly interact with endocytic adaptor protein-2 (AP2); thus, acting as negative competitors for the interaction between AP2 and P2X4, impairing constitutive P2X4 endocytosis. The higher P2X4 surface density was particularly observed in peripheral macrophages of SOD1 mice before the onset and during the progression of ALS symptoms positioning P2X4 as a potential early biomarker for ALS. P2X4 expression was also upregulated in spinal microglia of SOD1 mice during ALS and affect microglial inflammatory responses. Importantly, we report using double transgenic SOD1 mice expressing internalization-defective P2X4mCherryIN knock-in gene or invalidated for the P2X4 gene that P2X4 is instrumental for motor symptoms, ALS progression and survival. This study highlights the role of P2X4 in the pathophysiology of ALS and thus its potential for the development of biomarkers and treatments. We also decipher the molecular mechanism by which misfolded proteins related to ALS impact P2X4 trafficking at early pathological stage in cells expressing-P2X4.

AB - Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron (MN) disease characterized by protein misfolding and aggregation leading to cellular degeneration. So far neither biomarker, nor effective treatment has been found. ATP signaling and P2X4 receptors (P2X4) are upregulated in various neurodegenerative diseases. Here we show that several ALS-related misfolded proteins including mutants of SOD1 or TDP-43 lead to a significant increase in surface P2X4 receptor density and function in vitro. In addition, we demonstrate in the spinal the cord of SOD1-G93A (SOD1) mice that misfolded SOD1-G93A proteins directly interact with endocytic adaptor protein-2 (AP2); thus, acting as negative competitors for the interaction between AP2 and P2X4, impairing constitutive P2X4 endocytosis. The higher P2X4 surface density was particularly observed in peripheral macrophages of SOD1 mice before the onset and during the progression of ALS symptoms positioning P2X4 as a potential early biomarker for ALS. P2X4 expression was also upregulated in spinal microglia of SOD1 mice during ALS and affect microglial inflammatory responses. Importantly, we report using double transgenic SOD1 mice expressing internalization-defective P2X4mCherryIN knock-in gene or invalidated for the P2X4 gene that P2X4 is instrumental for motor symptoms, ALS progression and survival. This study highlights the role of P2X4 in the pathophysiology of ALS and thus its potential for the development of biomarkers and treatments. We also decipher the molecular mechanism by which misfolded proteins related to ALS impact P2X4 trafficking at early pathological stage in cells expressing-P2X4.

KW - Amyotrophic Lateral Sclerosis/genetics

KW - Animals

KW - Disease Models, Animal

KW - Disease Progression

KW - Mice

KW - Mice, Transgenic

KW - Motor Neuron Disease/genetics

KW - Motor Neurons/metabolism

KW - Receptors, Purinergic P2X4/genetics

KW - Spinal Cord/metabolism

KW - Superoxide Dismutase-1/genetics

U2 - 10.1007/s00018-022-04461-5

DO - 10.1007/s00018-022-04461-5

M3 - SCORING: Journal article

C2 - 35852606

VL - 79

JO - CELL MOL LIFE SCI

JF - CELL MOL LIFE SCI

SN - 1420-682X

IS - 8

M1 - 431

ER -