Treating Diseases correlated with or caused by Non-Physiological Levels of Microtubule-Associated PP2Ac
Hyper- or hypophosphorylation of proteins is known to be pathogenic in a variety of diseases. Most important examples include Alzheimer's disease and other neurodegenerative disorders such as Huntington's disease, but also cancerogenesis. In many cases (e.g. during the development of Alzheimer's disease and of different types of tumors) non-physiological levels and activity of microtubule-associated protein phosphatase 2A (PP2Ac) have been found to be the underlying biochemical defect. So far, although theoretically very effective in terms of Alzheimer's or tumor therapy, external manipulation of PP2Ac levels or activity was impossible due to tremendous toxic side effects for the cell.
We have identified a novel mechanism of cellular PP2Ac regulation that concentrates on the microtubule-associated pool of PP2Ac, and a more gentle possibility of efficient external manipulation of intracellular PP2Ac levels lacking severe cellular side effects.
Our data show, that MID1, a microtubule-associated RING-finger protein targets the ubiquitination machinery towards microtubule-associated PP2Ac by binding to its regulatory subunit α4 and thus regulates its degradation in a highly selective manner. Moreover, we could demonstrate that, using RNAi oligos or small peptides that disturbe the described mechanism, intracellular PP2Ac activity could be significantly increased and the phosphorylation status of various, disease-related proteins could be manipulated.
Patients with a defect in the respective mechanism (regulation of PP2Ac stability via MID1 / alpha4) show abnormal development of the ventral midline but have normal life spans which means that a drug therapy as described should not have severe side effects in adult patients. Thus our data indicate for the first time, that the highly specific, disease relevant pool of microtubule-associated PP2A is amenable for the development of urgently needed therapeutic interventions in areas such as e.g. Alzheimer's, Huntington's disease and cancer.
Interestingly, Rapamycin, a small molecule with shown anti-neurodegenerative potential is interfering with the regulatory interaction between MID1 and microtubule-associated PP2Ac underlining the importance and providing a proof of concept of the mechanism described here.
We are looking for a collaboration or licensing partner who is interested in this mechanism and is able to develop these exciting scientific results into marketable assets.