KCC2 as a novel biomarker and therapeutic target for motoneuron degenerative disease

Khademullah, C. S.; Bourbonnais, J.; Chaineau, M. M.; Castellanos Montiel, M. J.; Keramidis, I.; Legault, A.; Paquet, M.-E.; Abrahao, A.; Zinman, L.; Robertson, J.; Durcan, T.; Woodin, M. A.; Godin, A. G.; De Koninck, Y.

doi:10.1101/2023.08.24.554410

bioRxiv · 10.1101/2023.08.24.554410

KCC2 as a novel biomarker and therapeutic target for motoneuron degenerative disease

Khademullah, C. S.·Bourbonnais, J.·Chaineau, M. M.·Castellanos Montiel, M. J.·Keramidis, I.·Legault, A.·Paquet, M.-E.·Abrahao, A.·Zinman, L.·Robertson, J.·Durcan, T.·Woodin, M. A.·Godin, A. G.·De Koninck, Y.

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Abstract

Hyperexcitability in cells throughout the corticospinal tract is a presymptomatic feature of amyotrophic lateral sclerosis (ALS) associated with lethal motor degeneration 1-6. Disinhibition is a possible cause of this hyperexcitability, potentially implicating the central nervous system-specific potassium-chloride cotransporter, KCC2, a core regulator of the strength of GABAergic neurotransmission linked to several neurological disorders 7-11. Here, we show that KCC2 is downregulated in the membrane of motor cortex neurons from post-mortem SOD1-, C9orf72- and sporadic ALS is patients. Increased protein levels of KCC2 were found in plasma and cerebral spinal fluid of ALS patients and mice harbouring the SOD1*G93A mutation. Longitudinal analysis of disease progression in both SOD1*G93A and Prp-TDP43*A315T mice revealed a decrease of KCC2 membrane levels in cortical and spinal motor neurons which were already present at the presymptomatic phase. Using KCC2-enhancing compounds, CLP290 and prochlorperazine (PCPZ) restored KCC2 membrane expression and function, delayed motor deficit onset, and extended lifespan up to two months in mutant mice. Human-derived neurons differentiated from iPSC harbouring the SOD1*G93A mutation displayed KCC2 deficits which PCPZ treatment rescued. Acute administration of KCC2 enhancers restored chloride transport in presymptomatic and symptomatic mice and reversed motor neuron hyperexcitability in awake behaving mutant mice. These findings identify KCC2 as both an early biomarker and a disease-modifying therapeutic target for ALS.

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Khademullah, C. S., Bourbonnais, J., Chaineau, M. M., Castellanos Montiel, M. J., Keramidis, I., Legault, A., Paquet, M.-E., Abrahao, A., Zinman, L., Robertson, J., Durcan, T., Woodin, M. A., Godin, A. G., De Koninck, Y.. 2023-08-25. KCC2 as a novel biomarker and therapeutic target for motoneuron degenerative disease. https://doi.org/10.1101/2023.08.24.554410

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