PMID- 33561134
OWN - NLM
STAT- MEDLINE
DCOM- 20210708
LR  - 20210708
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 16
IP  - 2
DP  - 2021
TI  - Human INCL fibroblasts display abnormal mitochondrial and lysosomal networks and 
      heightened susceptibility to ROS-induced cell death.
PG  - e0239689
LID - 10.1371/journal.pone.0239689 [doi]
LID - e0239689
AB  - Infantile Neuronal Ceroid Lipofuscinosis (INCL) is a pediatric neurodegenerative 
      disorder characterized by progressive retinal and central nervous system 
      deterioration during infancy. This lysosomal storage disorder results from a 
      deficiency in the Palmitoyl Protein Thioesterase 1 (PPT1) enzyme-a lysosomal 
      hydrolase which cleaves fatty acid chains such as palmitate from lipid-modified 
      proteins. In the absence of PPT1 activity, these proteins fail to be degraded, 
      leading to the accumulation of autofluorescence storage material in the lysosome. 
      The underlying molecular mechanisms leading to INCL pathology remain poorly 
      understood. A role for oxidative stress has been postulated, yet little evidence 
      has been reported to support this possibility. Here we present a comprehensive 
      cellular characterization of human PPT1-deficient fibroblast cells harboring 
      Met1Ile and Tyr247His compound heterozygous mutations. We detected 
      autofluorescence storage material and observed distinct organellar abnormalities 
      of the lysosomal and mitochondrial structures, which supported previous 
      postulations about the role of ER, mitochondria and oxidative stress in INCL. An 
      increase in the number of lysosomal structures was found in INCL patient 
      fibroblasts, which suggested an upregulation of lysosomal biogenesis, and an 
      association with endoplasmic reticulum stress response. The mitochondrial network 
      also displayed abnormal spherical punctate morphology instead of normal elongated 
      tubules with extensive branching, supporting the involvement of mitochondrial and 
      oxidative stress in INCL cell death. Autofluorescence accumulation and lysosomal 
      pathologies can be mitigated in the presence of conditioned wild type media 
      suggesting that a partial restoration via passive introduction of the enzyme into 
      the cellular environment may be possible. We also demonstrated, for the first 
      time, that human INCL fibroblasts have a heightened susceptibility to exogenous 
      reactive oxygen species (ROS)-induced cell death, which suggested an elevated 
      basal level of endogenous ROS in the mutant cell. Collectively, these findings 
      support the role of intracellular organellar networks in INCL pathology, possibly 
      due to oxidative stress.
FAU - Balouch, Bailey
AU  - Balouch B
AUID- ORCID: 0000-0002-7016-1374
AD  - Neuroscience Program, Union College, Schenectady, New York, United States of 
      America.
FAU - Nagorsky, Halle
AU  - Nagorsky H
AD  - Neuroscience Program, Union College, Schenectady, New York, United States of 
      America.
FAU - Pham, Truc
AU  - Pham T
AD  - Department of Biology, Union College, Schenectady, New York, United States of 
      America.
FAU - LaGraff, James Thai
AU  - LaGraff JT
AD  - Department of Biology, Union College, Schenectady, New York, United States of 
      America.
FAU - Chu-LaGraff, Quynh
AU  - Chu-LaGraff Q
AUID- ORCID: 0000-0002-3002-3524
AD  - Neuroscience Program, Union College, Schenectady, New York, United States of 
      America.
AD  - Department of Biology, Union College, Schenectady, New York, United States of 
      America.
LA  - eng
PT  - Journal Article
DEP - 20210209
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Membrane Proteins)
RN  - 0 (Reactive Oxygen Species)
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)
SB  - IM
MH  - Apoptosis/genetics
MH  - Cell Death/genetics
MH  - Cells, Cultured
MH  - Endoplasmic Reticulum/metabolism
MH  - Fibroblasts/metabolism
MH  - Humans
MH  - Lysosomal Storage Diseases/metabolism/physiopathology
MH  - Lysosomes/metabolism
MH  - Membrane Proteins/genetics/*metabolism
MH  - Mitochondria/metabolism
MH  - Neurodegenerative Diseases/metabolism/physiopathology
MH  - Neuronal Ceroid-Lipofuscinoses/*metabolism/physiopathology
MH  - Oxidative Stress
MH  - Reactive Oxygen Species/metabolism
MH  - Thiolester Hydrolases/genetics/*metabolism
PMC - PMC7872282
COIS- The authors have declared that no competing interests exist.
EDAT- 2021/02/10 06:00
MHDA- 2021/07/09 06:00
PMCR- 2021/02/09
CRDT- 2021/02/09 17:12
PHST- 2020/09/07 00:00 [received]
PHST- 2021/01/09 00:00 [accepted]
PHST- 2021/02/09 17:12 [entrez]
PHST- 2021/02/10 06:00 [pubmed]
PHST- 2021/07/09 06:00 [medline]
PHST- 2021/02/09 00:00 [pmc-release]
AID - PONE-D-20-28154 [pii]
AID - 10.1371/journal.pone.0239689 [doi]
PST - epublish
SO  - PLoS One. 2021 Feb 9;16(2):e0239689. doi: 10.1371/journal.pone.0239689. 
      eCollection 2021.