PMID- 24056696
OWN - NLM
STAT- MEDLINE
DCOM- 20131227
LR  - 20211021
IS  - 1546-1726 (Electronic)
IS  - 1097-6256 (Print)
IS  - 1097-6256 (Linking)
VI  - 16
IP  - 11
DP  - 2013 Nov
TI  - Neuroprotection and lifespan extension in Ppt1(-/-) mice by NtBuHA: therapeutic 
      implications for INCL.
PG  - 1608-17
LID - 10.1038/nn.3526 [doi]
AB  - Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating childhood 
      neurodegenerative lysosomal storage disease (LSD) that has no effective 
      treatment. It is caused by inactivating mutations in the palmitoyl-protein 
      thioesterase-1 (PPT1) gene. PPT1 deficiency impairs the cleavage of thioester 
      linkage in palmitoylated proteins (constituents of ceroid), preventing 
      degradation by lysosomal hydrolases. Consequently, accumulation of lysosomal 
      ceroid leads to INCL. Thioester linkage is cleaved by nucleophilic attack. 
      Hydroxylamine, a potent nucleophilic cellular metabolite, may have therapeutic 
      potential for INCL, but its toxicity precludes clinical application. We found 
      that a hydroxylamine derivative, N-(tert-Butyl) hydroxylamine (NtBuHA), was 
      non-toxic, cleaved thioester linkage in palmitoylated proteins and mediated 
      lysosomal ceroid depletion in cultured cells from INCL patients. In Ppt1(-/-) 
      mice, which mimic INCL, NtBuHA crossed the blood-brain barrier, depleted 
      lysosomal ceroid, suppressed neuronal apoptosis, slowed neurological 
      deterioration and extended lifespan. Our findings provide a proof of concept that 
      thioesterase-mimetic and antioxidant small molecules such as NtBuHA are potential 
      drug targets for thioesterase deficiency diseases such as INCL.
FAU - Sarkar, Chinmoy
AU  - Sarkar C
AD  - 1] Section on Developmental Genetics, Program on Developmental Endocrinology and 
      Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human 
      Development, National Institutes of Health, Bethesda, Maryland, USA. [2].
FAU - Chandra, Goutam
AU  - Chandra G
FAU - Peng, Shiyong
AU  - Peng S
FAU - Zhang, Zhongjian
AU  - Zhang Z
FAU - Liu, Aiyi
AU  - Liu A
FAU - Mukherjee, Anil B
AU  - Mukherjee AB
LA  - eng
GR  - Z99 HD999999/Intramural NIH HHS/United States
GR  - ZIA HD000910-33/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20130922
PL  - United States
TA  - Nat Neurosci
JT  - Nature neuroscience
JID - 9809671
RN  - 0 (Carbon Isotopes)
RN  - 0 (Hydroxylamines)
RN  - 0 (N-(tert-butyl)hydroxylamine)
RN  - 0 (Neuroprotective Agents)
RN  - 1763-10-6 (Palmitoyl Coenzyme A)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (palmitoyl-protein thioesterase)
RN  - Ceroid lipofuscinosis, neuronal 1, infantile
SB  - IM
CIN - Nat Rev Drug Discov. 2013 Nov;12(11):828. PMID: 24136395
MH  - Animals
MH  - Apoptosis/drug effects/genetics
MH  - Carbon Isotopes/metabolism
MH  - Cells, Cultured
MH  - Cerebral Cortex/pathology
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Gene Expression Regulation/drug effects/genetics
MH  - Hydroxylamines/metabolism/pharmacology/*therapeutic use
MH  - Longevity/drug effects/genetics
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neuronal Ceroid-Lipofuscinoses/*drug therapy/*genetics/pathology
MH  - Neurons/drug effects/metabolism/ultrastructure
MH  - Neuroprotective Agents/metabolism/*therapeutic use
MH  - Palmitoyl Coenzyme A/drug effects/metabolism
MH  - Thiolester Hydrolases/*deficiency
MH  - Time Factors
PMC - PMC3812271
MID - NIHMS520270
EDAT- 2013/09/24 06:00
MHDA- 2013/12/29 06:00
PMCR- 2014/05/01
CRDT- 2013/09/24 06:00
PHST- 2013/06/05 00:00 [received]
PHST- 2013/08/23 00:00 [accepted]
PHST- 2013/09/24 06:00 [entrez]
PHST- 2013/09/24 06:00 [pubmed]
PHST- 2013/12/29 06:00 [medline]
PHST- 2014/05/01 00:00 [pmc-release]
AID - nn.3526 [pii]
AID - 10.1038/nn.3526 [doi]
PST - ppublish
SO  - Nat Neurosci. 2013 Nov;16(11):1608-17. doi: 10.1038/nn.3526. Epub 2013 Sep 22.