Neurodegenerative disease like Alzheimer's, Parkinson's, and ALS (amyotrophic lateral sclerosis) are debilitating conditions that affect millions of people worldwide every year. These pathologies are notoriously difficult to prevent or effectively treat due to a complex interplay of genetics, lifestyle, co-infection, and many other factors impacting everything from diagnosis to treatment.
While a comprehensive cure-all to these neurological conditions is unlikely, scientists are making headway into understanding their fundamental characteristics with the hope of preventing or alleviating cognitive and motor impairments. In a new study published in Science Advances , researchers from the Molecular Neuroscience Unit and the former Cellular and Molecular Synaptic Function Unit at the Okinawa Institute of Science and Technology (OIST) have now discovered that ATP, which is most commonly thought of as the 'fuel' of our cells, plays a surprising role in relation to neurodegenerative diseases. "We found that ATP regulates protein condensation and the overall viscosity of cytoplasm in neurons," says Dr. Laurent Guillaud, lead author of the study. When the cytoplasm in axons – or the axoplasm – is more viscous, proteins are more prone to aggregate, which can lead to harmful tangles that damage the cells. "Through both in vitro and in vivo trials, we found that boosting ATP production decreases cytosolic viscosity in affected cells, dispersing existing and preventing future pathological protein aggregations."
In many neurodegenerative diseases, one common symptom is the formation and accumulation of insoluble, membrane-less protein condensates via a process known as liquid-liquid phase separation. These protein aggregates can accumulate both inside and later outside the cells. For example, in late-stage Alzheimer's disease, these may appear as neurofibrillary tangles.
Recent research has shown that ATP may play a direct role in regulating protein solubilization in vitro and cytoplasmic viscosity in yeast cells, acting as an important hydrotropic agent: a compound that increases the solubility of other, poorly water-soluble substances – including various proteins. Now, through their in vitro and in vivo experiments on human stem cell-derived neurons from both healthy and Parkinson's and ALS patients, the team observed a direct relationship between the intracellular concentration of ATP and the solubility of the axoplasm and of proteins normally associated with neurodegenerative disorders, like SNCA in Parkinson's, Tau in Alzheimer's, and TDP-43 in ALS.
"Mammalian cells normally have an average ATP concentration of four to eight millimolar, which is surprisingly high, as the total concentration of ATP needed for all energy processes in the cell is only in the few hundreds of micromolar – an order of magnitude lower. This led us to focus on and examine the possible hydrotropic role of ATP in neurons, from which we found a remarkable correlation between the intracellular concentration of ATP and the axoplasmic viscosity in both physiological and pathological conditions," explains Dr. Guillaud. For example, the researchers showed that in physiological conditions, local variations in ATP can also affect the viscosity of the cytosol, of synaptic vesicles and of active zones in the presynaptic compartment, changing the functional organization of the synapse.
ATP is largely produced by mitochondria, and mitochondrial functions and the rate of ATP synthesis naturally declines throughout our lifespan. Problems arise when other factors negatively affect mitochondrial health such as in Parkinson's disease or ALS, which can lead to further reduction in the concentration of ATP, thereby decreasing the solubility of proteins and rendering the cytoplasm more viscous. As part of their experiments, the researchers found that boosting ATP production using NMN rescued cytosolic fluidity by breaking up and solubilizing existing protein aggregates in axons from ALS neurons.
Research into neurodegenerative diseases is highly complex given their multifaceted nature and while we are far from a comprehensive cure, key findings as reported by the researchers here have important implications for our understanding of the cellular mechanisms of the diseases, bringing us closer to one day being able to comprehensively prevent or treat these debilitating neurodegenerative disorders.
