Ultrastructural Abnormalities in Induced Pluripotent Stem Cell-Derived Neural Stem Cells and Neurons of Two Cohen Syndrome Patients

Shnaider, T.A.; Khabarova, A.A.; Morozova, K.N.; Yunusova, A.M.; Yakovleva, S.A.; Chvileva, A.S.; Wolf, E.R.; Kiseleva, E.V.; Grigor’eva, E.V.; Voinova, V.Y.; Lagarkova, M.A.; Pomerantseva, E.A.; Musatova, E.V.; Smirnov, A.V.; Smirnova, A.V.; Stoklitskaya, D.S.; Arefieva, T.I.; Larina, D.A.; Nikitina, T.V.; Pristyazhnyuk, I.E.

Авторы: Shnaider Tatiana A., Khabarova Anna A., Morozova Ksenia N., Yunusova Anastasia M., Yakovleva Sophia A., Chvileva Anastasia S., Wolf Ekaterina R., Kiseleva Elena V., Grigor’eva Elena V., Voinova Viktori Y., Lagarkova Maria A., Pomerantseva Ekaterina A., Musatova Elizaveta V., Smirnov Alexander V., Smirnova Anna V., Stoklitskaya Diana S., Arefieva Tatiana I., Larina Daria A., Nikitina Tatiana V., Pristyazhnyuk Inna E.
Журнал: Cells
Том: 12
Номер: 23
Год издания: 2023
Издательство: MDPI
Местоположение издательства: Basel, Switzerland
Номер статьи: 2702
DOI: 10.3390/cells12232702
Аннотация: Cohen syndrome is an autosomal recessive disorder caused by VPS13B (COH1) gene mutations. This syndrome is significantly underdiagnosed and is characterized by intellectual disability, microcephaly, autistic symptoms, hypotension, myopia, retinal dystrophy, neutropenia, and obesity. VPS13B regulates intracellular membrane transport and supports the Golgi apparatus structure, which is critical for neuron formation. We generated induced pluripotent stem cells from two patients with pronounced manifestations of Cohen syndrome and differentiated them into neural stem cells and neurons. Using transmission electron microscopy, we documented multiple new ultrastructural changes associated with Cohen syndrome in the neuronal cells. We discovered considerable disturbances in the structure of some organelles: Golgi apparatus fragmentation and swelling, endoplasmic reticulum structural reorganization, mitochondrial defects, and the accumulation of large autophagosomes with undigested contents. These abnormalities underline the ultrastructural similarity of Cohen syndrome to many neurodegenerative diseases. The cell models that we developed based on patient-specific induced pluripotent stem cells can serve to uncover not only neurodegenerative processes, but the causes of intellectual disability in general.
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Ultrastructural Abnormalities in Induced Pluripotent Stem Cell-Derived Neural Stem Cells and Neurons of Two Cohen Syndrome Patientsстатья Электронная публикация