TY - JOUR

T1 - Ultrastructural Abnormalities in Induced Pluripotent Stem Cell-Derived Neural Stem Cells and Neurons of Two Cohen Syndrome Patients

AU - Shnaider, Tatiana A

AU - Khabarova, Anna A

AU - Morozova, Ksenia N

AU - Yunusova, Anastasia M

AU - Yakovleva, Sophia A

AU - Chvileva, Anastasia S

AU - Wolf, Ekaterina R

AU - Kiseleva, Elena V

AU - Grigor'eva, Elena V

AU - Voinova, Viktori Y

AU - Lagarkova, Maria A

AU - Pomerantseva, Ekaterina A

AU - Musatova, Elizaveta V

AU - Smirnov, Alexander V

AU - Smirnova, Anna V

AU - Stoklitskaya, Diana S

AU - Arefieva, Tatiana I

AU - Larina, Daria A

AU - Nikitina, Tatiana V

AU - Pristyazhnyuk, Inna E

N1 - The reported study was supported by the Ministry of Science and Higher Education of the Russian Federation (state contract 075-15-2021-1063 from 28 September 2021). Confocal microscopy and TEM were performed at the Center of Collective Use for Microscopic Analysis of Biological Objects (ICG SB RAS, Novosibirsk, Russia) (FWNR-2022-0019).

PY - 2023/11/25

Y1 - 2023/11/25

N2 - 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.

AB - 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.

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85179372614&origin=inward&txGid=d8a0b72f8085bb048b609d6a41371d6c

U2 - 10.3390/cells12232702

DO - 10.3390/cells12232702

M3 - Article

C2 - 38067130

VL - 12

JO - Cells

JF - Cells

SN - 2073-4409

IS - 23

M1 - 2702

ER -