The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC and Fly Models of Parkinson’s Disease

David C Schöndorf,Dina Ivanyuk,Pascale Baden,Alvaro Sanchez-Martinez,Silvia De Cicco,Cong Yu,Ivana Giunta,Lukas K Schwarz,Gabriele Di Napoli,Vasiliki Panagiotakopoulou,Sigrun Nestel,Marcus Keatinge,Jan Pruszak,Oliver Bandmann,Bernd Heimrich,Thomas Gasser,Alexander J Whitworth,Michela Deleidi

doi:10.1016/j.celrep.2018.05.009

Abstract

While mitochondrial dysfunction is emerging as key in Parkinson's disease (PD), a central question remains whether mitochondria are actual disease drivers and whether boosting mitochondrial biogenesis and function ameliorates pathology. We address these questions using patient-derived induced pluripotent stem cells and Drosophila models of GBA-related PD (GBA-PD), the most common PD genetic risk. Patient neurons display stress responses, mitochondrial demise, and changes in NAD+ metabolism. NAD+ precursors have been proposed to ameliorate age-related metabolic decline and disease. We report that increasing NAD+ via the NAD+ precursor nicotinamide riboside (NR) significantly ameliorates mitochondrial function in patient neurons. Human neurons require nicotinamide phosphoribosyltransferase (NAMPT) to maintain the NAD+ pool and utilize NRK1 to synthesize NAD+ from NAD+ precursors. Remarkably, NR prevents the age-related dopaminergic neuronal loss and motor decline in fly models of GBA-PD. Our findings suggest NR as a viable clinical avenue for neuroprotection in PD and other neurodegenerative diseases.

Highlights

Mitochondrial dysfunction has been proposed as a key mechanism in many neurodegenerative diseases
IPSC-Derived Neurons from GBA-Parkinson’s disease (PD) Patients Show Defects in Mitochondrial Function To investigate whether GBA is linked to mitochondrial function in human neurons, induced pluripotent stem cell (iPSC) lines from PD patients with heterozygous GBA mutations (N370S, L444P, and RecNcil), as well as corresponding isogenic gene-corrected (GC) and unaffected controls (Schondorf et al, 2014) (Table S1), were differentiated into dopaminergic (DA) neurons, and mitochondrial morphology was examined by transmission electron microscopy (TEM)
Basal respiration, maximal oxygen consumption rates (OCRs), and ATP-linked OCR and spare respiratory capacity (SRC) were significantly reduced in GBA-related PD (GBA-PD) neurons compared to unrelated unaffected controls (Figure S1B)

Summary

Introduction

Mitochondrial dysfunction has been proposed as a key mechanism in many neurodegenerative diseases. Substantial progress has been made since, and genetic and biochemical studies indicate that mitochondrial dysfunction and cellular energy failure are key to PD (Jansen et al, 2017). 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 (SIRT1) pathway, provides protection against aging-related disease (Rajman et al, 2018). Similar approaches could be translated into treatment for PD It is still unclear whether mitochondrial defects are actual disease drivers and increasing mitochondrial biogenesis provides neuroprotection in PD. Patients with GBA mutations represent an etiologically homogeneous subgroup of PD, providing the ideal cohort for precision medicine approaches

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