@article{5d69d4b0f2ca463ab84640284d121e88,
title = "Exploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14)",
abstract = "Infantile neuroaxonal dystrophy (INAD) is caused by recessive variants in PLA2G6 and is a lethal pediatric neurodegenerative disorder. Loss of the Drosophila homolog of PLA2G6, leads to ceramide accumulation, lysosome expansion, and mitochondrial defects. Here, we report that retromer function, ceramide metabolism, the endolysosomal pathway, and mitochondrial morphology are affected in INAD patient-derived neurons. We show that in INAD mouse models, the same features are affected in Purkinje cells, arguing that the neuropathological mechanisms are evolutionary conserved and that these features can be used as biomarkers. We tested 20 drugs that target these pathways and found that Ambroxol, Desipramine, Azoramide, and Genistein alleviate neurodegenerative phenotypes in INAD flies and INAD patient-derived neural progenitor cells. We also develop an AAV-based gene therapy approach that delays neurodegeneration and prolongs lifespan in an INAD mouse model.",
author = "Guang Lin and Burak Tepe and Geoff McGrane and Tipon, {Regine C.} and Gist Croft and Leena Panwala and Amanda Hope and Liang, {Agnes J.H.} and Zhongyuan Zuo and Byeon, {Seul Kee} and Lily Wang and Akhilesh Pandey and Bellen, {Hugo J.}",
note = "Funding Information: We thank Dayna McKenzie and Drs. Josephine Wesely and Brigham Hartley from the New York Stem Cell Foundation Research Institute for their contribution to genetically correct the INAD patient-derived iPSCs. The authors thank Drs. Jin Xu for very insightful comments. The authors thank the Gene Vector Core at Baylor College of Medicine for packaging the AAV-PHP.eB virus. The authors thank the GERM Core at Baylor College of Medicine for the in vitro fertilization to retrieve the Pla2g6G373R mice. The authors are grateful for the generous gift of skin fibroblasts from Dr. B{\'e}n{\'e}dicte Heron (Neurologie P{\'e}diatrique H{\^o}pital Trousseau) and Dr. Young-Hui Jiang (Duke University). This project was supported in part by Baylor College of Medicine IDDRC Grant number P50HD103555 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development for use of the Microscopy Core facilities. The authors acknowledge the Shan and Lee-Jun Wong Fellowship to GL. The authors thank the INADcure Foundation for support to GL. HJB and the NYSCF. This project was also supported by the Huffington Foundation and the Jan and Dan Duncan Neurological Research Institute-Chair in Neurogenetics of TCH to HJB. Publisher Copyright: {\textcopyright} Lin et al.",
year = "2023",
month = jan,
doi = "10.7554/eLife.82555",
language = "English (US)",
volume = "12",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}