Novel therapies for neuromuscular diseases with altered phosphoinositide metabolism
Final Report Abstract
Within this project we have identified the lipid kinase PI3KC2b as a genetic and functional modifier of MTM1 function in a cell-based model of XLCNM. We have demonstrated that genetic KO of Pik3c2b or pharmacological inhibition of PI3KC2b activity rescues reduced active b1-integrin surface levels and other key phenotypes of MTM1 dysfunction such as defective myoblast differentiation and reduced numbers of FAs that underlie XLCNM pathology. Together with previous studies that have established a role for MTM1 in the delivery of b-integrins to the cell surface, our findings suggest a model whereby PI3KC2β and MTM1 antagonistically control active β1-integrin endocytosis and recycling to the plasma membrane from endosomes. A key role for b1-integrin endocytosis and recycling in centronuclear myopathy is underscored by the fact that gain-of-function mutations in the endocytic protein dynamin 2 that lead to elevated dynamin 2 protein levels cause an autosomal dominant form of the disease. Our studies also provide prima facie evidence that acute pharmacological inhibition of PI3KC2b activity can rescue key features of MTM1 deficiency and may therefore provide a therapeutic option for XLCNM patients. The development of specific class II PI 3-kinase inhibitors may serve as a starting point for the future development of small molecules that selectively interfere with PI3KC2b function at the organismic level. The tools developed here will serve to pave the way towards this goal. Moreover, our work does not support the idea that manipulation of PI3KC2b activity could act as a therapeutic option for non-XLCNM MTMopathies such as CMT4B, which appear to be mainly caused by elevated PI(3,5)P2 levels and resulting dysregulation of mTORC1 signaling and, possibly other pathways. We therefore suggest to further explore the potential use of PIKfyve inhibitors such as Apilimod and/ or mTORC1 inhibitors as a potential treatment option for CMT4B patients.
Publications
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2018) TAM4MTM: tamoxifen therapy in a murine model of myotubular myopathy. Nature Communications 9, 4849
Maani, N., Sabha, N., Rezai, K., Ramani, A., Groom, L., Eltayeb, N., Mavandadnejad, F., Pang, A., Russo, G., Brudno, M., Haucke, V. Dirksen, R.T., Dowling, J.J.
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(2020) Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth. Nat. Commun. 11, 2835
Sawade, L., Grandi, F., Mignanelli, M., Patiño-López, G., Klinkert, K., Langa -Vives, F., Di Guardo, R., Echard, A., Bolino, A., Haucke, V.
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(2021) Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy. Proc Natl Acad Sci USA 118, e2009469118
Guerrero-Valero, M., Grandi, F., Cipriani, S., Alberizzi, V., Di Guardo, R., Chicanne, G., Sawade, L., Bianci, F., Del Carro, U., De Curtis, I., Pareyson, D., Parman, Y., Schenone, A, Haucke, V., Payrastre, B., Bolino, A.
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(2021) The molecular mechanisms mediating class II PI 3-kinase function in cell physiology. FEBS J.
Koch, P.A., Dornan, G.L., Hessenberger, M., Haucke, V.
