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

Autor:	Lin G; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States., Tepe B; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States., McGrane G; New York Stem Cell Foundation Research Institute, New York, United States., Tipon RC; New York Stem Cell Foundation Research Institute, New York, United States., Croft G; New York Stem Cell Foundation Research Institute, New York, United States., Panwala L; INADcure Foundation, Jersey City, United States., Hope A; INADcure Foundation, Jersey City, United States., Liang AJH; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States., Zuo Z; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States., Byeon SK; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States., Wang L; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States., Pandey A; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States.; Manipal Academy of Higher Education, Manipal, Karnataka, India., Bellen HJ; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.; Department of Neuroscience, Baylor College of Medicine, Houston, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2023 Jan 16; Vol. 12. Date of Electronic Publication: 2023 Jan 16.
DOI:	10.7554/eLife.82555
Abstrakt:	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. Competing Interests: GL, BT, GM, RT, GC, LP, AH, AL, ZZ, SB, LW, AP No competing interests declared, HB Reviewing editor, eLife (© 2023, Lin et al.)
Databáze:	MEDLINE
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