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

Elife. 2023 Jan 16:12:e82555. doi: 10.7554/eLife.82555.


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.

Keywords: INAD; Parkinson's disease; adeno-associated virus; ceramides; dopaminergic neurons; drosophila; drug screen; gene therapy; ipsc; lysosome; mice; neural progenitor cells; neuroscience.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ceramides / metabolism
  • Drosophila / metabolism
  • Drosophila Proteins* / genetics
  • Drosophila Proteins* / metabolism
  • Eye Proteins / metabolism
  • Group VI Phospholipases A2 / metabolism
  • Mice
  • Neuroaxonal Dystrophies* / genetics
  • Neuroaxonal Dystrophies* / metabolism
  • Neuroaxonal Dystrophies* / pathology
  • Neurons / metabolism
  • Parkinsonian Disorders* / metabolism


  • Ceramides
  • Pla2g6 protein, mouse
  • Group VI Phospholipases A2
  • inaD protein, Drosophila
  • Eye Proteins
  • Drosophila Proteins

Supplementary concepts

  • Dystonia-Parkinsonism, Adult-Onset