PMID- 35150145
OWN - NLM
STAT- MEDLINE
DCOM- 20220511
LR  - 20230502
IS  - 1573-2665 (Electronic)
IS  - 0141-8955 (Print)
IS  - 0141-8955 (Linking)
VI  - 45
IP  - 3
DP  - 2022 May
TI  - Ppt1-deficiency dysregulates lysosomal Ca(++) homeostasis contributing to 
      pathogenesis in a mouse model of CLN1 disease.
PG  - 635-656
LID - 10.1002/jimd.12485 [doi]
AB  - Inactivating mutations in the PPT1 gene encoding palmitoyl-protein thioesterase-1 
      (PPT1) underlie the CLN1 disease, a devastating neurodegenerative lysosomal 
      storage disorder. The mechanism of pathogenesis underlying CLN1 disease has 
      remained elusive. PPT1 is a lysosomal enzyme, which catalyzes the removal of 
      palmitate from S-palmitoylated proteins (constituents of ceroid lipofuscin) 
      facilitating their degradation and clearance by lysosomal hydrolases. Thus, it 
      has been proposed that Ppt1-deficiency leads to lysosomal accumulation of ceroid 
      lipofuscin leading to CLN1 disease. While S-palmitoylation is catalyzed by 
      palmitoyl acyltransferases (called ZDHHCs), palmitoyl-protein thioesterases 
      (PPTs) depalmitoylate these proteins. We sought to determine the mechanism by 
      which Ppt1-deficiency may impair lysosomal degradative function leading to 
      infantile neuronal ceroid lipofuscinosis pathogenesis. Here, we report that in 
      Ppt1(-/-) mice, which mimic CLN1 disease, low level of inositol 3-phosphate 
      receptor-1 (IP3R1) that mediates Ca(++) transport from the endoplasmic reticulum 
      to the lysosome dysregulated lysosomal Ca(++) homeostasis. Intriguingly, the 
      transcription factor nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4), 
      which regulates IP3R1-expression, required S-palmitoylation for trafficking from 
      the cytoplasm to the nucleus. We identified two palmitoyl acyltransferases, 
      ZDHHC4 and ZDHHC8, which catalyzed S-palmitoylation of NFATC4. Notably, in 
      Ppt1(-/-) mice, reduced ZDHHC4 and ZDHHC8 levels markedly lowered S-palmitoylated 
      NFATC4 (active) in the nucleus, which inhibited IP3R1-expression, thereby 
      dysregulating lysosomal Ca(++) homeostasis. Consequently, Ca(++) -dependent 
      lysosomal enzyme activities were markedly suppressed. Impaired lysosomal 
      degradative function impaired autophagy, which caused lysosomal storage of 
      undigested cargo. Importantly, IP3R1-overexpression in Ppt1(-/-) mouse 
      fibroblasts ameliorated this defect. Our results reveal a previously unrecognized 
      role of Ppt1 in regulating lysosomal Ca(++) homeostasis and suggest that this 
      defect contributes to pathogenesis of CLN1 disease.
CI  - Published 2022. This article is a U.S. Government work and is in the public 
      domain in the USA.
FAU - Mondal, Avisek
AU  - Mondal A
AD  - Section on Developmental Genetics, Division of Translational Medicine, Eunice 
      Kennedy Shriver National Institute of Child Health and Human Development, The 
      National Institutes of Health, Bethesda, Maryland, USA.
FAU - Appu, Abhilash P
AU  - Appu AP
AD  - Section on Developmental Genetics, Division of Translational Medicine, Eunice 
      Kennedy Shriver National Institute of Child Health and Human Development, The 
      National Institutes of Health, Bethesda, Maryland, USA.
FAU - Sadhukhan, Tamal
AU  - Sadhukhan T
AD  - Section on Developmental Genetics, Division of Translational Medicine, Eunice 
      Kennedy Shriver National Institute of Child Health and Human Development, The 
      National Institutes of Health, Bethesda, Maryland, USA.
FAU - Bagh, Maria B
AU  - Bagh MB
AD  - Section on Developmental Genetics, Division of Translational Medicine, Eunice 
      Kennedy Shriver National Institute of Child Health and Human Development, The 
      National Institutes of Health, Bethesda, Maryland, USA.
FAU - Previde, Rafael M
AU  - Previde RM
AD  - Section on Cellular Signaling, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, The National Institutes of Health, Bethesda, 
      Maryland, USA.
FAU - Sadhukhan, Sriparna
AU  - Sadhukhan S
AD  - Section on Developmental Genetics, Division of Translational Medicine, Eunice 
      Kennedy Shriver National Institute of Child Health and Human Development, The 
      National Institutes of Health, Bethesda, Maryland, USA.
FAU - Stojilkovic, Stanko
AU  - Stojilkovic S
AD  - Section on Cellular Signaling, Eunice Kennedy Shriver National Institute of Child 
      Health and Human Development, The National Institutes of Health, Bethesda, 
      Maryland, USA.
FAU - Liu, Aiyi
AU  - Liu A
AD  - Biostatistics and Bioinformatics Branch, Division of Intramural Population Health 
      Research, Eunice Kennedy Shriver National Institute of Child Health and Human 
      Development, The National Institutes of Health, Bethesda, Maryland, USA.
FAU - Mukherjee, Anil B
AU  - Mukherjee AB
AUID- ORCID: 0000-0003-4445-5464
AD  - Section on Developmental Genetics, Division of Translational Medicine, Eunice 
      Kennedy Shriver National Institute of Child Health and Human Development, The 
      National Institutes of Health, Bethesda, Maryland, USA.
LA  - eng
GR  - ZIA HD000910/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20220317
PL  - United States
TA  - J Inherit Metab Dis
JT  - Journal of inherited metabolic disease
JID - 7910918
RN  - 0 (Lipofuscin)
RN  - 0 (Membrane Proteins)
RN  - EC 2.3.- (Acyltransferases)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (PPT1 protein, human)
RN  - EC 3.1.2.22 (palmitoyl-protein thioesterase)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Acyltransferases
MH  - Animals
MH  - Calcium/*metabolism
MH  - Disease Models, Animal
MH  - Homeostasis
MH  - Humans
MH  - *Lipofuscin
MH  - Lysosomes/metabolism
MH  - Membrane Proteins
MH  - Mice
MH  - Mice, Knockout
MH  - *Neuronal Ceroid-Lipofuscinoses/genetics/pathology
MH  - Thiolester Hydrolases/genetics/*metabolism
PMC - PMC9090967
MID - NIHMS1780119
OTO - NOTNLM
OT  - Batten disease
OT  - S-palmitoylation
OT  - infantile neuronal ceroid lipofuscinosis
OT  - lysosomal storage disease
OT  - neurodegeneration
OT  - neuronal ceroid lipofuscinosis
OT  - palmitoyl-protein thioesterase-1
COIS- Competing interests. All authors declare no competing interest in this research.
EDAT- 2022/02/13 06:00
MHDA- 2022/05/12 06:00
PMCR- 2023/05/01
CRDT- 2022/02/12 08:33
PHST- 2022/02/05 00:00 [revised]
PHST- 2021/10/08 00:00 [received]
PHST- 2022/02/08 00:00 [accepted]
PHST- 2022/02/13 06:00 [pubmed]
PHST- 2022/05/12 06:00 [medline]
PHST- 2022/02/12 08:33 [entrez]
PHST- 2023/05/01 00:00 [pmc-release]
AID - 10.1002/jimd.12485 [doi]
PST - ppublish
SO  - J Inherit Metab Dis. 2022 May;45(3):635-656. doi: 10.1002/jimd.12485. Epub 2022 
      Mar 17.