PMID- 36645408
OWN - NLM
STAT- MEDLINE
DCOM- 20230202
LR  - 20230322
IS  - 2050-084X (Electronic)
IS  - 2050-084X (Linking)
VI  - 12
DP  - 2023 Jan 16
TI  - Exploring therapeutic strategies for infantile neuronal axonal dystrophy 
      (INAD/PARK14).
LID - 10.7554/eLife.82555 [doi]
LID - e82555
AB  - 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.
CI  - (c) 2023, Lin et al.
FAU - Lin, Guang
AU  - Lin G
AUID- ORCID: 0000-0001-5594-3397
AD  - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 
      United States.
AD  - Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 
      Houston, United States.
FAU - Tepe, Burak
AU  - Tepe B
AUID- ORCID: 0000-0003-4371-2502
AD  - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 
      United States.
AD  - Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 
      Houston, United States.
FAU - McGrane, Geoff
AU  - McGrane G
AD  - New York Stem Cell Foundation Research Institute, New York, United States.
FAU - Tipon, Regine C
AU  - Tipon RC
AUID- ORCID: 0000-0002-5473-7353
AD  - New York Stem Cell Foundation Research Institute, New York, United States.
FAU - Croft, Gist
AU  - Croft G
AD  - New York Stem Cell Foundation Research Institute, New York, United States.
FAU - Panwala, Leena
AU  - Panwala L
AD  - INADcure Foundation, Jersey City, United States.
FAU - Hope, Amanda
AU  - Hope A
AD  - INADcure Foundation, Jersey City, United States.
FAU - Liang, Agnes J H
AU  - Liang AJH
AD  - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 
      United States.
AD  - Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 
      Houston, United States.
FAU - Zuo, Zhongyuan
AU  - Zuo Z
AD  - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 
      United States.
AD  - Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 
      Houston, United States.
FAU - Byeon, Seul Kee
AU  - Byeon SK
AD  - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United 
      States.
FAU - Wang, Lily
AU  - Wang L
AD  - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 
      United States.
AD  - Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 
      Houston, United States.
FAU - Pandey, Akhilesh
AU  - Pandey A
AUID- ORCID: 0000-0001-9943-6127
AD  - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United 
      States.
AD  - Manipal Academy of Higher Education, Manipal, Karnataka, India.
FAU - Bellen, Hugo J
AU  - Bellen HJ
AUID- ORCID: 0000-0001-5992-5989
AD  - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 
      United States.
AD  - Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 
      Houston, United States.
AD  - Department of Neuroscience, Baylor College of Medicine, Houston, United States.
LA  - eng
GR  - P50 HD103555/HD/NICHD NIH HHS/United States
GR  - P50HD103555/NH/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230116
PL  - England
TA  - Elife
JT  - eLife
JID - 101579614
RN  - 0 (Ceramides)
RN  - EC 3.1.1.4 (Pla2g6 protein, mouse)
RN  - EC 3.1.1.4 (Group VI Phospholipases A2)
RN  - 0 (inaD protein, Drosophila)
RN  - 0 (Eye Proteins)
RN  - 0 (Drosophila Proteins)
RN  - Dystonia-Parkinsonism, Adult-Onset
SB  - IM
MH  - Mice
MH  - Animals
MH  - Neurons/metabolism
MH  - *Parkinsonian Disorders/metabolism
MH  - Drosophila/metabolism
MH  - Ceramides/metabolism
MH  - *Neuroaxonal Dystrophies/genetics/metabolism/pathology
MH  - Group VI Phospholipases A2/metabolism
MH  - Eye Proteins/metabolism
MH  - *Drosophila Proteins/genetics/metabolism
PMC - PMC9889087
OTO - NOTNLM
OT  - INAD
OT  - Parkinson's disease
OT  - adeno-associated virus
OT  - ceramides
OT  - dopaminergic neurons
OT  - drosophila
OT  - drug screen
OT  - gene therapy
OT  - ipsc
OT  - lysosome
OT  - mice
OT  - neural progenitor cells
OT  - neuroscience
COIS- GL, BT, GM, RT, GC, LP, AH, AL, ZZ, SB, LW, AP No competing interests declared, 
      HB Reviewing editor, eLife
EDAT- 2023/01/17 06:00
MHDA- 2023/02/03 06:00
PMCR- 2023/01/16
CRDT- 2023/01/16 10:52
PHST- 2022/08/09 00:00 [received]
PHST- 2023/01/15 00:00 [accepted]
PHST- 2023/01/17 06:00 [pubmed]
PHST- 2023/02/03 06:00 [medline]
PHST- 2023/01/16 10:52 [entrez]
PHST- 2023/01/16 00:00 [pmc-release]
AID - 82555 [pii]
AID - 10.7554/eLife.82555 [doi]
PST - epublish
SO  - Elife. 2023 Jan 16;12:e82555. doi: 10.7554/eLife.82555.