Exploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14)

• Published in: eLife 2023-01, Vol.12
• Main Authors: Lin, Guang, Tepe, Burak, McGrane, Geoff, Tipon, Regine C, Croft, Gist, Panwala, Leena, Hope, Amanda, Liang, Agnes J H, Zuo, Zhongyuan, Byeon, Seul Kee, Wang, Lily, Pandey, Akhilesh, Bellen, Hugo J
• Format: Article
• Language: English
• Subjects: Analysis; Animal models; Animals; Antibodies; Ceramide; ceramides; Ceramides - metabolism; Desipramine; Drosophila - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; drug screen; Dystonia; Dystrophy; Evolutionary conservation; Eye Proteins - metabolism; Fibroblasts; Gene therapy; Genistein; Group VI Phospholipases A2 - metabolism; Health aspects; INAD; INAD protein; Life span; lysosome; Mice; Mitochondria; Molecular weight; Mutation; Nervous system; Nervous system diseases; Neural stem cells; Neuroaxonal Dystrophies - genetics; Neuroaxonal Dystrophies - metabolism; Neuroaxonal Dystrophies - pathology; Neurodegeneration; Neurodegenerative diseases; Neurons; Neurons - metabolism; Neuropathology; Neuroscience; Parkinson's disease; Parkinsonian Disorders - metabolism; Patients; Pediatrics; Phenotypes; Physiological aspects; Progenitor cells; Purkinje cells; Scientific equipment and supplies industry
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.82555

Infantile neuroaxonal dystrophy (INAD) is caused by recessive variants in and is a lethal pediatric neurodegenerative disorder. Loss of the homolog of , 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.