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

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. Mito...

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Bibliographic Details
Published in:Cell death & disease 2020-03, Vol.11 (3), p.182-182, Article 182
Main Authors: Winanto, Khong, Zi Jian, Soh, Boon-Seng, Fan, Yong, Ng, Shi-Yan
Format: Article
Language:English
Subjects:
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Acidosis
Antibodies
Axonogenesis
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
Central nervous system
Deoxyribonucleic acid
DNA
Humans
Immunology
Lactic acidosis
Life Sciences
MELAS syndrome
MELAS Syndrome - genetics
Mitochondrial DNA
Mutation
Nervous System Diseases - genetics
Neurogenesis
Neurons - metabolism
Organoids
Organoids - metabolism
Pluripotency
Secretase
Skeletal muscle
Spinal cord
Stem cells
Stroke-like episodes
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Summary: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.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-020-2383-6