New Discoveries Show ATP's Role in Combating Protein Aggregation in Parkinson's and ALS

Recent scientific advancements have shed light on the critical role of adenosine triphosphate (ATP), commonly known as the energy currency of cells, in neurodegenerative diseases like Parkinson's disease and amyotrophic lateral sclerosis (ALS). Researchers at the Okinawa Institute of Science and Technology (OIST) have uncovered that ATP not only supplies energy but also actively influences the physical properties of neurons, particularly regulating the viscosity of the cytoplasm and preventing harmful protein aggregation.

Neurodegenerative disorders such as Alzheimer's, Parkinson's, and ALS share a common feature: the accumulation of insoluble protein aggregates inside and outside neurons, forming structures like neurofibrillary tangles or protein condensates. These aggregates disrupt normal cell function and are associated with cognitive and motor impairments. The new study demonstrates that ATP acts as a hydrotropic agent, a molecule that increases the solubility of proteins, thereby reducing their tendency to clump together.

Dr. Laurent Guillaud, the lead author, explains that ATP controls the condensation process of proteins and influences the viscosity within neurons. When ATP levels decline, often due to mitochondrial dysfunction common in aging and disease, the cytoplasm becomes more viscous, making proteins more prone to aggregation. The team’s experiments revealed that boosting ATP production in neurons—especially using precursors like NMN (nicotinamide mononucleotide)—can decrease cytosolic viscosity, dissolve existing protein aggregates, and prevent the formation of new harmful clumps.

Their in vitro and in vivo studies on human stem cell-derived neurons from healthy individuals, as well as Parkinson's and ALS patients, confirmed a direct link between intracellular ATP concentration and protein solubility. Notably, increasing ATP levels reduced the aggregation of proteins such as TDP-43, Tau, and SNCA, which are associated with these neurodegenerative diseases. The findings indicate that maintaining or enhancing ATP production within neurons could be a promising strategy to preserve cellular health and combat disease progression.

Furthermore, the research highlights that local fluctuations in ATP influence the organization and function of synapses by affecting the fluidity of the cytosol and vesicle mobility. Since mitochondrial function declines with age, resulting in decreased ATP synthesis, restoring ATP levels might offer a therapeutic avenue. In fact, the application of NMN was shown to restore extracellular fluidity, breaking down protein aggregates in damaged neurons.

While complete cures for neurodegenerative diseases remain elusive due to their complex nature, these discoveries provide vital insight into the cellular mechanisms driving disease pathology. Enhancing ATP levels could be an innovative way to reduce protein aggregation and maintain neuronal health, potentially delaying or alleviating symptoms associated with Parkinson’s and ALS.

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