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

Abstract

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.

Exploring the pathological mechanisms underlying Cohen syndrome

“…In another study, iPSC-derived neurons from two CS patients using an alternative differentiation protocol revealed ultrastructural defects in several organelles beyond the Golgi, including altered morphology of ER and mitochondria, as well as increased MCS between these organelles. An impairment in autophagic flux was also noted, which aligns with elevated cellular stress and potential neurodegeneration ( Shnaider et al, 2023 ). Given the well-known heterogenicity of iPSC lines, these studies (each using fibroblasts from only one or two patients) require further validation to fully establish how well they recapitulate the pathological mechanism of the disease at the cellular level.…”