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

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Infantile neuroaxonal dystrophy (INAD) is a severe pediatric neurodegenerative disorder caused by recessive variants in the PLA2G6 gene.
• Loss of the PLA2G6 homolog in Drosophila results in ceramide accumulation, lysosomal enlargement, and mitochondrial dysfunction.

Purpose of the Study:

• To investigate the cellular mechanisms underlying INAD.
• To identify potential therapeutic targets and treatments for INAD.

Main Methods:

• Analysis of patient-derived neurons and INAD mouse models to examine cellular pathways.
• Drug screening targeting affected pathways in Drosophila and patient-derived neural progenitor cells.
• Development and testing of AAV-based gene therapy in a mouse model.

Main Results:

• Patient neurons and INAD mouse models exhibit defects in retromer function, ceramide metabolism, endolysosomal pathways, and mitochondrial morphology.
• These cellular defects are evolutionarily conserved and can serve as biomarkers.
• Ambroxol, Desipramine, Azoramide, and Genistein demonstrated efficacy in alleviating neurodegenerative phenotypes.
• AAV-mediated gene therapy successfully delayed neurodegeneration and extended lifespan in the INAD mouse model.

Conclusions:

• Cellular pathways including ceramide metabolism and endolysosomal function are critical in INAD pathogenesis.
• Targeting these pathways with specific drugs or gene therapy offers potential therapeutic strategies for INAD.