Exploring Therapeutic Strategies for Infantile Neuronal Axonal Dystrophy (INAD/PARK14)

Authors

Guang Lin
Burak Tepe
Geoff McGrane
Regine C Tipon
Gist Croft
Leena Panwala
Amanda Hope
Agnes J H Liang
Zhongyuan Zuo
Seul Kee Byeon
Lily Wang
Akhilesh Pandey
Hugo J Bellen

Publication Date

1-16-2023

Journal

eLife

DOI

10.7554/eLife.82555

PMID

36645408

PMCID

PMC9889087

PubMedCentral® Posted Date

1-16-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Drosophila Proteins, Ceramides, Parkinsonian Disorders, Drosophila, Dystonic Disorders, Group VI Phospholipases A2, Mice, Animals, Neuroaxonal Dystrophies, Eye Proteins, Neurons, Drosophila, IPSC, Neural progenitor cells, Dopaminergic neurons, Mice, Adeno-associated virus

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.