Exploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/ PARK14 ).
Guang LinBurak TepeGeoff McGraneRegine C TiponGist CroftLeena PanwalaAmanda HopeAgnes J H LiangZhongyuan ZuoSeul Kee ByeonLily WangAkhilesh PandeyHugo J BellenPublished in: eLife (2023)
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 NPCs. We also develop an AAV-based gene therapy approach that delays neurodegeneration and prolongs lifespan in an INAD mouse model.
Keyphrases
- mouse model
- gene therapy
- oxidative stress
- induced apoptosis
- early onset
- spinal cord injury
- spinal cord
- transcription factor
- young adults
- copy number
- endoplasmic reticulum stress
- genome wide
- cell cycle arrest
- brain injury
- cell death
- dna methylation
- autism spectrum disorder
- signaling pathway
- fluorescent probe
- blood brain barrier
- living cells
- optic nerve