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Neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS), impose significant challenges on millions globally every year. These conditions are marked by their complexity, influenced by a myriad of factors such as genetics, lifestyle choices, co-infections, and more, complicating their diagnosis and treatment.
Although a universal cure remains elusive, researchers are making strides in deciphering the underlying mechanisms of these disorders, aiming to mitigate the cognitive and motor decline associated with them. A recent study published in Science Advances by the Molecular Neuroscience Unit and the former Cellular and Molecular Synaptic Function Unit at the Okinawa Institute of Science and Technology (OIST) highlights an unexpected role for ATP, often dubbed the ‘energy currency’ of cells, in the context of neurodegenerative diseases. “Our findings indicate that ATP is crucial in regulating protein condensation and the viscosity of neuronal cytoplasm,” explains Dr. Laurent Guillaud, the study’s lead author. The research uncovered that increased viscosity in axonal cytoplasm, also known as axoplasm, can lead to protein aggregation, forming toxic tangles detrimental to neuron function. “Our experiments, both in vitro and in vivo, demonstrate that enhancing ATP production can reduce cytosolic viscosity in troubled cells, thereby dispersing existing aggregates and preventing further accumulation,” adds Dr. Guillaud.
In various neurodegenerative diseases, a hallmark observation is the buildup of insoluble, membrane-less protein aggregates through a process called liquid-liquid phase separation. These aggregates can form both inside the neurons and in extracellular spaces; neurofibrillary tangles, for instance, are a key feature of advanced Alzheimer’s disease.
Contemporary research suggests that ATP might directly influence protein solubilization in vitro and the viscosity of cytoplasm in yeast cells, functioning as a hydrotropic agent—substances that enhance the solubility of poorly hydrophilic compounds, including proteins. By conducting experiments on neurons derived from human stem cells from both healthy individuals and those diagnosed with Parkinson’s and ALS, the researchers identified a clear association between ATP levels within cells and both the solubility of axoplasm and the proteins involved in these neurodegenerative conditions, including SNCA in Parkinson’s, Tau in Alzheimer’s, and TDP-43 in ALS.
“Typically, mammalian cells maintain an ATP concentration of four to eight millimolar, which is surprisingly high given that the energy demands of the cell require only hundreds of micromolar—a significant difference. This observation prompted us to investigate the potential hydrotropic effect of ATP in neurons,” Dr. Guillaud elaborates. Their research unveiled that variations in ATP levels can influence cytosolic viscosity as well as the properties of synaptic vesicles and active zones, affecting the synapse’s functional architecture.
ATP is primarily produced in mitochondria, and as we age, mitochondrial efficiency and ATP synthesis rates diminish. This decline can be exacerbated by various factors that impair mitochondrial health—ailments such as Parkinson’s and ALS further contribute to ATP deficits, resulting in decreased protein solubility and heightened cytoplasmic viscosity. The research team discovered that augmenting ATP production with NMN effectively restored cytosolic fluidity, aiding in the disaggregation and solubilization of existing protein accumulations in ALS-afflicted axons.
Investigating neurodegenerative disorders is inherently complicated due to their multifaceted characteristics. Although the goal of developing a holistic cure remains a distant prospect, the pivotal insights from this research pave the way for a deeper understanding of the cellular processes involved, steering us closer to potential preventive and therapeutic strategies for these debilitating conditions.
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