Synucleinopathies such as Parkinson’s disease are caused by the spread of misfolded α-synuclein through the brain. α-synuclein is one of a small number of proteins that, when misfolded, can encourage other molecules of the same protein to misfold in the same way, aggregating to form toxic solid deposits and a halo of disrupted biochemistry. Misfolded α-synuclein is particularly pernicious as it can pass from cell to cell, spreading pathology as it goes. Here, researchers explore one of the ways in which misfolded α-synuclein harms cells, by interfering in the supply of the energy store molecule adenosine triphosphate (ATP) that is produced by mitochondria and is essential to cell function.
Parkinson’s disease (PD) is the second most common neurodegenerative disorder and the most frequent movement disorder today, for which there is only symptomatic treatment. Amyloid fibers of the protein α-synuclein (αSyn) constitute the major content of pathological intraneuronal inclusions, Lewy bodies, found in dopaminergic neurons in PD patient brains. Amyloid toxicity has been attributed to the ability to seed new amyloids, to translocate between cells, to deteriorate membranes, to be a sink for functionally relevant proteins by binding, and to sterically block cellular functions. Amyloids were considered chemically inert until we showed that αSyn amyloids catalyzed hydrolysis of ester and phosphoester bonds in vitro.
Lewy pathology, i.e., amyloids, is also found in the nuclei of cells, and our earlier work showed αSyn monomers to interact with DNA. When we extended this to amyloids, we found that αSyn amyloid interactions with DNA promote strand breaks in the DNA. Thus, the chemical reactivity of αSyn amyloids may contribute to the noted widespread DNA damage observed in PD patients.
Neurons have disproportionately high energy demands compared to other organs but lack energy fuel storage (such as fatty acids and glucogen). In contrast to many other cells, neurons must continuously produce ATP from glucose to meet the cellular demands and maintain energy homeostasis. Decline in brain ATP levels has been connected to both Alzheimer’s and PD. There is evidence that αSyn amyloids perturb mitochondria, resulting in lower ATP production.
Here, we combine biochemical, biophysical, computational, and structural methods to probe the interaction between αSyn amyloids and ATP. We report that αSyn amyloids display catalytic activity toward ATP hydrolysis in vitro. We propose that ATP depletion by αSyn amyloid hydrolysis may disturb the local energy balance in neuronal cells.
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