Abstract-Text (inkl. Referenzen)

Mutations in POLG, encoding for the only mammalian mitochondrial DNA polymerase (Polymerase-γ), result in POLG-spectrum disorders (POLG-SDs), ranging from severe diseases like Alpers-Huttenlocher syndrome (AHS) to milder forms like Progressive external ophthalmoplegia (PEO). Most frequent recessive inherited mutations causing these disorders are p.A467T and p.W748S, resulting in mitochondrial impairment. POLG-SD patients show symptoms like epilepsy, myopathy and hepatic failure. There is no cure.
As possible therapeutic approaches, this study comprises the collection of POLG-SD affected patients" fibroblasts and the characterization of mitochondrial function. This allows the examination of different approaches to stimulate the mitochondrial biogenesis (MB) with the overall aim to improve mitochondrial health. The experimental procedure covers the application of the off-label drugs AICAR, Resveratrol, Formoterol, MitoQ and Cilostazol, which are known to stimulate MB. On the genetic level, genes that are important regulators of the MB, e.g. POLG, POLG2, TWINKLE, PPARGC1A, SSBP1 and TFAM, will be upregulated. With the described pharmacological and genetic strategies mitochondrial health in diseased cells might ameliorate.
The results from this study will serve as the fundament to find treatments for more common neurodegenerative diseases, also connected to mitochondrial dysfunction, such as Alzheimer"s and Parkinson"s Disease.