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Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons

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Mar 25, 2025 version files 446.66 KB

Abstract

Neurodegenerative diseases display synaptic deficits, mitochondrial defects, and protein aggregation. We show that intracellular ATP regulates axoplasmic viscosity and protein aggregation in mammalian neurons. Decreased intracellular ATP upon mitochondria inhibition leads to axo-terminal cytosol, synaptic vesicles, and active zone components condensation, modulating the functional organization of mouse glutamatergic synapses. Proteins involved in the pathogenesis of Parkinson’s disease (PD), Alzheimer's disease (AD), and Amyotrophic Lateral Sclerosis (ALS) condensed and underwent ATP-dependent LPS in vitro. Human iPSC-derived neurons from PD and ALS patients displayed a reduction in their axoplasmic fluidity and decreased intracellular ATP. Finally, nicotinamide mono-nucleotide (NMN) treatment successfully rescued intracellular ATP levels and axoplasmic viscosity in neurons from PD and ALS patients, and reduced TDP-43 aggregation in human motor neurons derived from an ALS patient. Thus, our data suggest that the hydrotropic activity of ATP contributes to the regulation of neuronal homeostasis in both physiological and pathological conditions.