The NAD Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC derived Cortical Organoid of Alpers' Disease.

Charalampos Tzoulis, Kristina Xiao Liang, Jiri Zeman, Evandro Fei Fang, Laurence A Bindoff, Yu Hong, Zhuoyuan Zhang, Tsering Yangzom, Anbin Chen, Bjørn Christian Lundberg, Richard Siller, Gareth John Sullivan

Journal: International journal of biological sciences 2024;20(4):1194-1217

PMID: 38385069

Free Full Text on PubMed Central View on PubMed

Abstract

Alpers' syndrome is an early-onset neurodegenerative disorder usually caused by biallelic pathogenic variants in the gene encoding the catalytic subunit of polymerase-gamma (POLG), which is essential for mitochondrial DNA (mtDNA) replication. The disease is progressive, incurable, and inevitably it leads to death from drug-resistant status epilepticus. The neurological features of Alpers' syndrome are intractable epilepsy and developmental regression, with no effective treatment; the underlying mechanisms are still elusive, partially due to lack of good experimental models. Here, we generated the patient derived induced pluripotent stem cells (iPSCs) from one Alpers' patient carrying the compound heterozygous mutations of A467T (c.1399G>A) and P589L (c.1766C>T), and further differentiated them into cortical organoids and neural stem cells (NSCs) for mechanistic studies of neural dysfunction in Alpers' syndrome. Patient cortical organoids exhibited a phenotype that faithfully replicated the molecular changes found in patient postmortem brain tissue, as evidenced by cortical neuronal loss and depletion of mtDNA and complex I (CI). Patient NSCs showed mitochondrial dysfunction leading to ROS overproduction and downregulation of the NADH pathway. More importantly, the NAD precursor nicotinamide riboside (NR) significantly ameliorated mitochondrial defects in patient brain organoids. Our findings demonstrate that the iPSC model and brain organoids are good models of Alpers' disease; this first-in-its-kind stem cell platform for Alpers' syndrome enables therapeutic exploration and has identified NR as a viable drug candidate for Alpers' disease and, potentially, other mitochondrial diseases with similar causes.

Address: Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway.; Neuro-SysMed, Center of Excellence for Clinical Research in Neurological Diseases, Haukeland University Hospital, Bergen, Norway.; Department of Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, China.; Department of Head and Neck Cancer Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China.; Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway.; Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway.; Neuro-SysMed, Center of Excellence for Clinical Research in Neurological Diseases, Haukeland University Hospital, Bergen, Norway.; Centre for International Health, University of Bergen, Bergen, Norway.; Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway.; Neuro-SysMed, Center of Excellence for Clinical Research in Neurological Diseases, Haukeland University Hospital, Bergen, Norway.; Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway.; Neuro-SysMed, Center of Excellence for Clinical Research in Neurological Diseases, Haukeland University Hospital, Bergen, Norway.; Department of Clinical Molecular Biology, Akershus University Hospital, University of Oslo, Oslo, Norway.; Department of Clinical Molecular Biology, Akershus University Hospital, University of Oslo, Oslo, Norway.; The Norwegian Centre on Healthy Ageing, Oslo, Norway.; Norwegian Center for Stem Cell Research, University of Oslo, 0317, Oslo, Norway.; Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317, Oslo, Norway.; Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317, Oslo, Norway.; Institute of Immunology, Oslo University Hospital, Oslo, Norway.; Department of Pediatric Research, Oslo University Hospital, Oslo, Norway.; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University, Prague, Czech Republic.; Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway.; Neuro-SysMed, Center of Excellence for Clinical Research in Neurological Diseases, Haukeland University Hospital, Bergen, Norway.; KG Jebsen Center for Parkinson's disease, University of Bergen, Bergen, Norway.; Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway.; Department of Neurology, Haukeland University Hospital, Bergen, Norway.; National Advisory Unit for Congenital Metabolic Diseases, Oslo University Hospital, Oslo, Norway.

DOI: 10.7150/ijbs.91624

Link outs

Free resources

Full Text Sources:

Medical:

https://medlineplus.gov/mitochondrialdiseases.html

Molecular Biology Databases:

https://data.niaid.nih.gov/resources?id=gse207007

MeSH Terms: Humans, DNA Polymerase gamma, NAD, Induced Pluripotent Stem Cells, Diffuse Cerebral Sclerosis of Schilder, DNA, Mitochondrial, Mutation, Mitochondrial Diseases, Niacinamide, Pyridinium Compounds