Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons
Summary
Neurodegenerative diseases display synaptic deficits, mitochondrial defects, and protein aggregation. We show that intracellular adenosine triphosphate (ATP) regulates axoplasmic viscosity and protein aggregation in mammalian neurons. Decreased intracellular ATP upon mitochondrial inhibition leads to axoterminal cytosol, synaptic vesicles, and active zone component 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 liquid phase separation in vitro. Human inducible pluripotent stem cell-derived neurons from patients with PD and ALS displayed reduced axoplasmic fluidity and decreased intracellular ATP. Last, nicotinamide mononucleotide treatment successfully rescued intracellular ATP levels and axoplasmic viscosity in neurons from patients with PD and ALS and reduced TAR DNA-binding protein 43 (TDP-43) aggregation in human motor neurons derived from a patient with ALS. Thus, our data suggest that the hydrotropic activity of ATP contributes to the regulation of neuronal homeostasis under both physiological and pathological conditions.
| Authors | Guillaud L, Garanzini A, Zakhia S, De la Fuente S, Dimitrov D, Boerner S, Terenzio M |
|---|---|
| Journal | Science advances |
| Publication Date | 2025 Apr 25;11(17):eadq6077 |
| PubMed | 40267187 |
| PubMed Central | PMC12017319 |
| DOI | 10.1126/sciadv.adq6077 |