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1. A pathogenic mutation in the ALS/FTD gene VCP induces mitochondrial hypermetabolism by modulating the permeability transition pore.

Author

Vanderhaeghe S, Prerad J, Tharkeshwar AK, Goethals E, Vints K, Beckers J, Scheveneels W, Debroux E, Princen K, Van Damme P, Fivaz M, Griffioen G, and Van Den Bosch L

Subjects
Humans, Cell Line, Tumor, Membrane Potential, Mitochondrial genetics, Mitochondrial Membrane Transport Proteins genetics, Mitochondrial Membrane Transport Proteins metabolism, Calcium metabolism, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis metabolism, Amyotrophic Lateral Sclerosis pathology, Valosin Containing Protein genetics, Valosin Containing Protein metabolism, Frontotemporal Dementia genetics, Frontotemporal Dementia metabolism, Frontotemporal Dementia pathology, Mitochondria metabolism, Mitochondria pathology, Mitochondrial Permeability Transition Pore metabolism, Mutation
Abstract

Valosin-containing protein (VCP) is a ubiquitously expressed type II AAA + ATPase protein, implicated in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This study aimed to explore the impact of the disease-causing VCP R191Q/wt mutation on mitochondrial function using a CRISPR/Cas9-engineered neuroblastoma cell line. Mitochondria in these cells are enlarged, with a depolarized mitochondrial membrane potential associated with increased respiration and electron transport chain activity. Our results indicate that mitochondrial hypermetabolism could be caused, at least partially, by increased calcium-induced opening of the permeability transition pore (mPTP), leading to mild mitochondrial uncoupling. In conclusion, our findings reveal a central role of the ALS/FTD gene VCP in maintaining mitochondrial homeostasis and suggest a model of pathogenesis based on progressive alterations in mPTP physiology and mitochondrial energetics., (© 2024. The Author(s).)

Published
2024
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2. Pharmacological modulation of septins restores calcium homeostasis and is neuroprotective in models of Alzheimer's disease.

Author

Princen K, Van Dooren T, van Gorsel M, Louros N, Yang X, Dumbacher M, Bastiaens I, Coupet K, Dupont S, Cuveliers E, Lauwers A, Laghmouchi M, Vanwelden T, Carmans S, Van Damme N, Duhamel H, Vansteenkiste S, Prerad J, Pipeleers K, Rodiers O, De Ridder L, Claes S, Busschots Y, Pringels L, Verhelst V, Debroux E, Brouwer M, Lievens S, Tavernier J, Farinelli M, Hughes-Asceri S, Voets M, Winderickx J, Wera S, de Wit J, Schymkowitz J, Rousseau F, Zetterberg H, Cummings JL, Annaert W, Cornelissen T, De Winter H, De Witte K, Fivaz M, and Griffioen G

Subjects
Animals, Humans, Mice, Calcium Channels metabolism, Calcium Signaling drug effects, Cytoskeleton metabolism, Cytoskeleton drug effects, Disease Models, Animal, Neuronal Plasticity drug effects, Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Calcium metabolism, Homeostasis, Neuroprotective Agents pharmacology, Neuroprotective Agents therapeutic use, Septins metabolism, tau Proteins metabolism
Abstract

Abnormal calcium signaling is a central pathological component of Alzheimer's disease (AD). Here, we describe the identification of a class of compounds called ReS19-T, which are able to restore calcium homeostasis in cell-based models of tau pathology. Aberrant tau accumulation leads to uncontrolled activation of store-operated calcium channels (SOCCs) by remodeling septin filaments at the cell cortex. Binding of ReS19-T to septins restores filament assembly in the disease state and restrains calcium entry through SOCCs. In amyloid-β and tau-driven mouse models of disease, ReS19-T agents restored synaptic plasticity, normalized brain network activity, and attenuated the development of both amyloid-β and tau pathology. Our findings identify the septin cytoskeleton as a potential therapeutic target for the development of disease-modifying AD treatments.

Published
2024
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