Enhancing mitochondrial biogenesis and function in Parkinson's disease

Identification: Deleidi, Michela


Enhancing mitochondrial biogenesis and function in Parkinson's disease

M. Deleidi1,*, D. C. Schöndorf2, D. Ivanyuk3, P. Baden3, A. Sanchez-Martinez4, S. De Cicco3, C. Yu1, L. Schwarz5, G. Di Napoli1, V. Panagiotakopoulou1, S. Nestel6, B. Heimrich6, T. Gasser1, A. Whitworth4 
1German Ctr. For Neurodegenerative Diseases/Dzne, Tübingen, Germany;  2Neurodegeneration, DZNE Tübingen, Tuebingen, Germany; 3DZNE, Tuebingen, Germany; 4MRC-MBU Cambridge, Cambridge, United Kingdom; 5Lukas Schwarz, Tübingen, Germany; 6Dept. of Neuroanatomy, Univ. of Freiburg, Freiburg, Germany

While mitochondrial dysfunction is emerging as key in Parkinson's disease (PD), a central question remains whether mitochondria are actual disease drivers and boosting mitochondrial biogenesis and function ameliorates pathology. Here, we address these questions using patient-derived induced pluripotent stem cells (iPSCs) and Drosophila models of GBA-related PD (GBA-PD), the most common PD genetic risk. Patient-derived neurons as well as neurons from GBA knockout iPSCs, generated by CRISPR-Cas9 technology, show defects in mitochondrial morphology and function. In addition, patient-derived neurons display a significant increase of endoplasmic reticulum stress responses and changes in NAD+ metabolism. In this respect, recent studies have shown that the activation of pathways related to mitochondrial biogenesis and energy metabolism, such as the NAD+/Sirtuin 1 pathway, provides protection against ageing-related disease. Here, we show that human neurons rely on nicotinamide phosphoribosyltransferase (NAMPT) for maintenance of the basal NAD+ pool, they are responsive to NAD+ precursors and utilize NRK1 as the main metabolic pathway to synthetize NAD+ from NAD+ precursors in a NAMPT independent manner. Increasing intracellular NAD+ concentrations via the NAD+ precursor nicotinamide riboside (NR) significantly ameliorates mitochondrial function in patient neurons. Importantly, NR prevents the age-related dopaminergic neuronal loss and motor decline in fly models of GBA-PD. Our study reveals mitochondrial dysfunction as a key driver of disease and suggests NR as a viable clinical avenue for neuroprotection in PD and other neurodegenerative diseases.


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