Build-up of linearly arranged orthophosphate units, polyphosphate (polyP) is a molecule of many functions. For instance, in mammalian cells it was shown to have a role in blood clotting, apoptosis, DNA repair, immune response and cancer. Recently our lab was able to identify that polyP is a potential modifier of neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD). The diseases have little in common apart from the fact that they occur later in life and that they are caused by amyloidogenic proteins (amyloid beta and Tau, and alpha-synuclein, respectively). The shared fiber formation mechanism of these proteins starts with the unfolding of the native monomer. These unfolded peptides form intermediate oligomers and protofibrils and eventually mature fibers. Most recent work shows the intermediate oligomers and protofibrils to be the toxic species that leads to apoptosis of neuronal cells.
Our lab was able to show that polyP significantly accelerates the fiber formation process of Aβ and Tau (AD) as well as of α-synuclein (PD) and protects neuronal cells in cell culture from their toxic effect. Based on these findings we believe that polyP might decrease or diminish toxicity by clearing the cell of the toxic intermediate species. Arthur Kornberg- the pioneer in the polyphosphate field- identified that polyP levels are present in the brain between 25 to 120 µM (per Pi). Recent work shows that these levels decrease with aging raising the hypothesis that polyP might be a physiologically relevant modifier of neurodegeneration and that restoration of polyP levels in older individuals might be beneficial for the progression or outcome of the disease.
In order to further test this hypothesis we are currently working on identifying the underlying mechanism of how polyP is able to accelerate the fiber formation of the Aβ, Tau and α-synuclein peptides, that have structurally and sequentially little in common. In cell culture we try to test how polyP is able to protect neuronal cells against the toxicity of amyloids. In collaboration with the Galvan lab, we are also examining histological and behavioral changes in the brains of AD model mice in the presence of exogenous polyP. In human brain tissue samples of asymptomatic AD, symptomatic AD and age-matched control patients, we are also comparing the amount and length of polyP present in different brain regions with the presence of amyloid plaques and recorded AD symptom severity.