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Organoid cultures of MELAS neural cells reveal hyperactive Notch signaling that impacts neurodevelopment.

ABSTRACT: Mutations in mitochondrial DNA (mtDNA), typically maternally inherited, can result in severe neurological conditions. There is currently no cure for mitochondrial DNA diseases and treatments focus on management of the symptoms rather than correcting the defects downstream of the mtDNA mutation. Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is one such mitochondrial disease that affects many bodily systems, particularly the central nervous system and skeletal muscles. Given the motor deficits seen in MELAS patients, we investigate the contribution of motor neuron pathology to MELAS. Using a spinal cord organoid system derived from induced pluripotent stem cells of a MELAS patient, as well as its isogenically corrected control, we found that high levels of Notch signaling underlie neurogenesis delays and neurite outgrowth defects that are associated with MELAS neural cultures. Furthermore, we demonstrate that the gamma-secretase inhibitor DAPT can reverse these neurodevelopmental defects.

SUBMITTER: Winanto

PROVIDER: S-EPMC7069952 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Organoid cultures of MELAS neural cells reveal hyperactive Notch signaling that impacts neurodevelopment.

Winanto Khong Zi Jian ZJ Soh Boon-Seng BS Fan Yong Y Ng Shi-Yan SY Ng Shi-Yan SY

Cell death & disease 20200313 3

Mutations in mitochondrial DNA (mtDNA), typically maternally inherited, can result in severe neurological conditions. There is currently no cure for mitochondrial DNA diseases and treatments focus on management of the symptoms rather than correcting the defects downstream of the mtDNA mutation. Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is one such mitochondrial disease that affects many bodily systems, particularly the central nervous system and skeletal m ...[more]

PMID: 32170107

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Project description:BackgroundThere are inconsistent reports regarding the association between general anesthesia and adverse neurodevelopmental and behavioral disorders in children.MethodsThis nationwide administrative cohort study included children born in Korea between 2008 and 2009, and followed until December 31, 2017. The cohort included 93,717 participants who received general anesthesia with endotracheal intubation (ETI) who were matched to unexposed subjects in a 1:1 ratio. General anesthesia was defined by National Health Insurance Service treatment codes with intratracheal anesthesia, and the index date was the first event of general anesthesia. The primary outcome was attention deficit hyperactive disorder (ADHD), which was defined as at least a principal diagnosis of 10th revision of the International Classification of Diseases code F90.X after the age of 72 months. Neurodevelopment, which was assessed using a developmental screening test (Korean-Ages and Stages Questionnaire [K-ASQ]), was a secondary outcome. The K-ASQ is performed annually from 1 to 6 years of age and consists of 5 domains. The association between general anesthesia and ADHD was estimated using a Cox hazard model, and its association with neurodevelopment was estimated using a generalized estimation equation, with control for multiple risk factors beyond 1 year after the index date.ResultsThe median age at the index date was 3.8 (95% confidence interval [CI], 1.7-5.8) years, and there were 57,625 (61.5%) men. During a mean follow-up period of 5 years, the incidence rate of ADHD was 42.6 and 27.7 per 10,000 person-years (PY) in the exposed and unexposed groups, respectively (absolute rate difference 14.9 [95% CI, 12.5-17.3] per 10,000 PY). Compared to the unexposed group, the exposed group had an increased risk of ADHD (adjusted hazard ratio, 1.41 [95% CI, 1.30-1.52]). In addition, a longer duration of anesthesia with ETI and more general anesthesia procedures with ETI were associated with greater risk of ADHD. General anesthesia with ETI was also associated with poorer results in the K-ASQ.ConclusionAdministration of general anesthesia with ETI to children is associated with an increased risk of ADHD and poor results in a neurodevelopmental screening test.

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Organoid cultures of MELAS neural cells reveal hyperactive Notch signaling that impacts neurodevelopment.

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Organoid cultures of MELAS neural cells reveal hyperactive Notch signaling that impacts neurodevelopment.

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