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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F24%3A10479906" target="_blank" >RIV/00216208:11110/24:10479906 - isvavai.cz</a>

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=JsD_iY9pCv" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=JsD_iY9pCv</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.7150/ijbs.91624" target="_blank" >10.7150/ijbs.91624</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

Alpers&apos; 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&apos; 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&apos; patient carrying the compound heterozygous mutations of A467T (c.1399G&gt;A) and P589L (c.1766C&gt;T), and further differentiated them into cortical organoids and neural stem cells (NSCs) for mechanistic studies of neural dysfunction in Alpers&apos; 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&apos; disease; this first-in-its-kind stem cell platform for Alpers&apos; syndrome enables therapeutic exploration and has identified NR as a viable drug candidate for Alpers&apos; disease and, potentially, other mitochondrial diseases with similar causes.

Název v anglickém jazyce

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

Popis výsledku anglicky

Alpers&apos; 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&apos; 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&apos; patient carrying the compound heterozygous mutations of A467T (c.1399G&gt;A) and P589L (c.1766C&gt;T), and further differentiated them into cortical organoids and neural stem cells (NSCs) for mechanistic studies of neural dysfunction in Alpers&apos; 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&apos; disease; this first-in-its-kind stem cell platform for Alpers&apos; syndrome enables therapeutic exploration and has identified NR as a viable drug candidate for Alpers&apos; disease and, potentially, other mitochondrial diseases with similar causes.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30209 - Paediatrics

Projekt

<a href="/cs/project/TO01000215" target="_blank" >TO01000215: Validace specifických biomarkerů mitofagie v kontinuu Alzheimerovy nemoci</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

International Journal of Biological Sciences

ISSN

1449-2288

e-ISSN

1449-2288

Svazek periodika

20

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

AU - Austrálie

Počet stran výsledku

24

Strana od-do

1194-1217

Kód UT WoS článku

001163043200010

EID výsledku v databázi Scopus

2-s2.0-85184463063