TY - JOUR
T1 - The NAD+ precursor nicotinamide riboside rescues mitochondrial defects and neuronal loss in iPSC derived cortical organoid of Alpers' disease
AU - Hong, Yu
AU - Zhang, Zhuoyuan
AU - Yangzom, Tsering
AU - Chen, Anbin
AU - Lundberg, Bjørn Christian
AU - Fang, Evandro Fei
AU - Siller, Richard
AU - Sullivan, Gareth John
AU - Zeman, Jiri
AU - Tzoulis, Charalampos
AU - Bindoff, Laurence A
AU - Liang, Kristina Xiao
N1 - Funding: This work was supported by the following funding: K.L was partly supported by University of Bergen Meltzers Høyskolefonds (#103517133) and Gerda Meyer Nyquist Legat (#103816102). L.A.B was supported the Norwegian Research Council (#229652), Rakel og Otto Kr.Bruuns legat. G.J.S was partly supported by the Norwegian Research Council through its Centres of Excellence funding scheme (#262613). E.F.F. is supported by Cure Alzheimer's Fund (#282952), HELSE SØR-ØST (#2020001, #2021021, #2023093), the Research Council of Norway (#262175, #334361), Molecule AG/VITADAO (#282942), NordForsk Foundation (#119986), the National Natural Science Foundation of China (#81971327), Akershus University Hospital (#269901, #261973, #262960), the Civitan Norges Forskningsfond for Alzheimers sykdom (#281931), the Czech Republic-Norway KAPPA programme (with Martin Vyhnálek, #TO01000215), and the Rosa sløyfe/Norwegian Cancer Society & Norwegian Breast Cancer Society (#207819). Z.Y.Z. is supported by the National Natural Science Foundation of China (#82103460).
PY - 2024/1/25
Y1 - 2024/1/25
N2 - 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 in vitro 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.
AB - 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 in vitro 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.
KW - Humans
KW - DNA polymerase gamma
KW - NAD/genetics
KW - Induced pluripotent stem cells
KW - Diffuse cerebral sclerosis of Schilder
KW - DNA, Mitochondrial/genetics
KW - Mutation
KW - Mitochondrial diseases
KW - Niacinamide/analogs & derivatives
KW - Pyridinium compounds
U2 - 10.7150/ijbs.91624
DO - 10.7150/ijbs.91624
M3 - Article
C2 - 38385069
SN - 1449-2288
VL - 20
SP - 1194
EP - 1217
JO - International Journal of Biological Sciences
JF - International Journal of Biological Sciences
IS - 4
ER -