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bioRxiv · 10.1101/2025.09.08.674945

Dysregulation of energy metabolism and calcium homeostasis in iPSC-derived neurons carrying Presenilin-1 M146L gene mutation

Wilson, C.·Galeano, P.·Remedi, M. M.·Novack, G. V.·Campanelli, L.·Gastaldi, L.·Miglietta, E. A.·Rossi, A. H.·Olivar, N.·Brusco, L. I.·Castano, E. M.·Caceres, A.·Morelli, L.
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Abstract

Impaired cellular activities, particularly in highly active cells such as neurons, are primarily supported by metabolic abnormalities and failures in Ca{superscript 2} homeostasis. Here, we provide an integrative analysis of human iPSC-derived neurons (iNs) carrying the Presenilin-1 M146L gene mutation (PS1M146L) and control cells (PS1control). PS1M146L iNs exhibited abnormal Ca{superscript 2} dynamics, a significant increase in key parameters of mitochondrial respiration, and higher intracellular ROS levels. KCl-evoked depolarisation was significantly lower in PS1M146L, suggesting a failure in maintaining the electrochemical gradient across the plasma membrane. Following thapsigargin stimulation, mitochondrial Ca{superscript 2} levels ([Ca{superscript 2}]m) were significantly reduced in PS1M146L, while [Ca{superscript 2}]m did not differ significantly between genotypes after treatment with bradykinin, suggesting that impairments in the [Ca{superscript 2}]m homeostasis are particularly evident under stress conditions and do not impact the 1,4,5-triphosphate (IP3) pathway. Since iNs of both genotypes were sensitive to the MCU-1 inhibitor, the deficits observed in PS1M146L could be the consequence of impairments in the ER-mitochondria contacts. Our results illustrate the utility of iNs carrying PS1 mutations in understanding how human neurons alter relevant pathways before neurodegeneration.

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Wilson, C., Galeano, P., Remedi, M. M., Novack, G. V., Campanelli, L., Gastaldi, L., Miglietta, E. A., Rossi, A. H., Olivar, N., Brusco, L. I., Castano, E. M., Caceres, A., Morelli, L.. 2025-09-14. Dysregulation of energy metabolism and calcium homeostasis in iPSC-derived neurons carrying Presenilin-1 M146L gene mutation. https://doi.org/10.1101/2025.09.08.674945

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