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Gabriele Saretzki

Gabriele Saretzki

University of Newcastle upon Tyne, UK

Title: Telomerase activators improve motor function and protein degradation in a mouse model of Parkinson′s disease

Biography

Biography: Gabriele Saretzki

Abstract

While telomerase maintains telomeres in dividing cells, its protein component TERT (telomerase reverse transcriptase) has various non-canonical functions such as localisation to mitochondria resulting in decreased oxidative stress, apoptosis and DNA damage. TERT protein persist in adult neurons while telomerase activity is downregulated early during development. We recently demonstrated increased mitochondrial TERT protein in hippocampal neurons from Alzheimer’s disease brains and mutual exclusion of pathological tau and TERT. Transduction of mutated tau into cultivated neurons confirmed that TERT decreases mitochondrial oxidative stress and lipid oxidation. Mitochondrial dysfunction is also involved in the development of other neurodegenerative diseases. Treatment of Parkinson’s disease (PD) model mice overexpressing human wild-type alpha-synuclein with 2 telomerase activators resulted in increased TERT expression in brain and amelioration of PD symptoms by significantly improving balance, gait and motor function as well as mitochondrial function. Analysing levels of total and phosphorylated alpha-synuclein we found a substantial decrease of both proteins in the hippocampus and neocortex suggesting a better protein degradation after telomerase activator treatment. Interaction of TERT with proteasomal and autophagy pathways has been described recently. Accordingly, we found a decrease in poly-ubiquitinated proteins and the autophagy receptor p62 and analyse the involvement of these degradation pathways currently. We also present data on DNA damage, telomere-associated foci (TAFs), BDNF, MnSOD, mitochondrial proteins and aggregated alpha synuclein in different brain regions. Thus, our results suggest that telomerase activators might form novel treatment options for better degradation of toxic proteins in neurodegenerative diseases such as PD and AD.