Progressive degeneration of human neural stem cells caused by pathogenic LRRK2

Aging and its physiological manifestations have been correlated with adult stem cell exhaustion and a failure to maintain tissue homeostasis1-10. Since multiple morphological cellular defects are associated with aging-related disorders, we hypothesized that late onset disorders might be linked to adult stem cell abnormalities compromising cellular function over time. Our work shows that a dominant G2019S mutation in the human LRRK2 gene, which is associated with central nervous system disorders, including Parkinson’s disease, the second most prevalent neurodegenerative disease in the aging population, causes alterations in neural stem cell homeostasis in aging-related cellular contexts. They include disruption of the nuclear architecture, deficiencies in clonal expansion and alterations in neural differentiation assays as well as an increased susceptibility to proteasomal stress. These phenotypic changes are dependent on differential kinase activity manifested during cellular passaging. Our studies might open new venues for studying the influence of aging in neural stem cell dependent processes, such as cognitive impairments, in the degenerating diseased brain.