Speaker
Description
Ataxia-telangiectasia (A-T) is a rare, autosomal recessive disorder affecting multiple systems, characterized by progressive cerebellar atrophy, neurodegeneration, and cognitive decline. A key neuropathological feature is the loss of Purkinje and granule cells in the cerebellum. Mutations in the ATM gene, located on chromosome 11q22-23, underlie A-T. This gene encodes ATM, a serine/threonine kinase involved in DNA repair and cell cycle regulation, impacting numerous substrates.
Our prior work has shown that human induced pluripotent stem cell-derived neural progenitor cells (hNPCs) possess self-renewal and multipotency, differentiating into both functional neurons and glial cells. Using CRISPR/Cas9 gene editing, we generated ATM-deficient hNPCs. Initial findings indicate that these ATM knockout hNPCs exhibit reduced proliferation and/or survival compared to wild-type hNPCs. Current investigations are focused on characterizing the ATM-deficient hNPCs, specifically examining established signaling pathways linked to ATM. We are also exploring the functional impact of ATM loss on hNPCs and their differentiated neuronal and non-neuronal progeny.
While the role of ATM in DNA damage repair and cell cycle control has been extensively studied in A-T patients and animal models, the precise molecular mechanisms driving neuronal and glial dysfunction in this disease remain to be fully elucidated. Given the absence of a targeted therapy for A-T, our research aims to identify novel cellular pathways disrupted by ATM deficiency in neural cells. This work seeks to uncover potential therapeutic targets for pharmacological intervention. Ultimately, ATM-deficient hNPCs offer a promising in vitro model to advance our understanding of A-T pathophysiology and facilitate drug discovery efforts.
| Author(s) | Emanuela Pessolano1,2*, Giulia Boni1,2, Giulia Dematteis1, Tiziana Ravasanenga1, Giulia Lecchi3, Camilla D’Angelo1,2, Carla Distasi1, Luigia Fresu3, Dmitry Lim1, Mariagrazia Grilli1,2 |
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| Affiliation(s) | 1Department of Pharmaceutical Sciences, 2Laboratory of Neuroplasticity, University of Piemonte Orientale, Novara, Italy. 3Department of Health Sciences, School of Medicine, University of Piemonte Orientale, Novara, Italy. |
