CLN7 mutation causes aberrant redistribution of protein isoforms and contributes to Batten disease pathobiology
Year: 2022
Type: preprint
Abstract: The variant late infantile form of the inherited neurodegenerative Batten disease (BD) is caused by mutations in the CLN7/MFSD8 gene and represents a strong candidate for gene therapy. Post-natal intracerebral administration of AAV9-hCLN7 to Cln7 Δex2 knockout mice resulted in extended lifespan but dose escalation resulted in reduced acuity in neurophysiology tests, cerebral atrophy and elevated neuroinflammation. Comparing patient and control iPSC-derived neural progenitor cells (iNPC) we discovered that CLN7 localizes to the nucleus as well as the endolysosomal network and is differentially distributed in BD iNPC. Proteomics identified a profound nuclear defect in BD iNPC that compounds with mitochondrial and lysosomal metabolic defects resulting in elevated apoptosis. We further identified a 50kDa common nuclear CLN7 isoform and a 37kDa isoform that accumulates only in BD iNPC nuclei. Our findings suggest that successful treatment of CLN7 BD will require combinatorial therapies addressing both loss and aberrant gain of protein function.
Authors: Aseel M. Sharaireh, Marta Guevara-Ferrer, Saul Herranz-Martin, Marina Garcia-Macia, Alexander Phillips, Anna Tierney, Michael P Hughes, Oliver Coombe-Tennant, Hemanth Nelvagel, Alysha E. Burrows, Stuart Fielding, Lorna M. FitzPatrick, Christopher D. Thornton, Stephan Storch, Sara E. Mole, Andrew Dowsey, Richard Unwin, Juan P. Bolanos, Ahad A. Rahim, Tristan R. McKay
Institutions: University of Jordan, Manchester Metropolitan University, University of Manchester, UCL School of Pharmacy, University College London, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca, Instituto de Biología Funcional y Genómica, University Medical Center Hamburg-Eppendorf, University of Liverpool, University of Bristol, Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Wellcome Trust, NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research, Action Medical Research, National Institute for Health and Care Research, King's College London, University College London, European Commission, Medical Research Council, Great Ormond Street Institute of Child Health, NIHR Great Ormond Street Hospital Biomedical Research Centre
Awards: G1660044801, Institutional Strategic Support Fund, G1854469666, G3195165511, G3323682383, Gene therapy for CLN5 Batten disease, Developing new therapies for Batten disease, G4338937870, G4477160695, G4719527389, The development of gene therapy for Niemann-Pick type C disease, G5157801895, G561437257, G6303889366, G6305404279, The development of gene therapy for infantile neuroaxonal dystrophy, Institutional Strategic Support Fund, Assessing the impact of host and virus genetic variability on Filovirus cell entry and infectivity, MICA: Towards clinical trial readiness of gene therapy for Niemann-Pick disease type c, G7507496763, G7741012721, G8145696578, G830246384
OpenAlex ID: W4280609407