PMID- 16242638
OWN - NLM
STAT- MEDLINE
DCOM- 20060123
LR  - 20071114
IS  - 0969-9961 (Print)
IS  - 0969-9961 (Linking)
VI  - 20
IP  - 2
DP  - 2005 Nov
TI  - Progressively reduced synaptic vesicle pool size in cultured neurons derived from 
      neuronal ceroid lipofuscinosis-1 knockout mice.
PG  - 314-23
AB  - The neuronal ceroid lipofuscinoses are a newly-recognized group of lysosomal 
      storage disorders in which neurodegeneration predominates. The pathophysiological 
      basis for this is unknown. In the current paper, we sought to determine whether 
      neurons that lack the enzyme responsible for the infantile form of neuronal 
      ceroid lipofuscinosis (INCL) display abnormalities in culture that could be 
      related to the clinical disorder. Electrophysiological and fluorescent dye 
      studies were performed using cortical neuronal cultures established from 
      postnatal day 2 palmitoyl-protein thioesterase-1 (Ppt1) knockout mice. We found a 
      30% reduction in synaptic vesicle number per bouton that was progressive with 
      time in culture as well as an elevation in lysosomal pH, whereas a number of 
      passive and active membrane properties of the neurons were normal. The reduction 
      in vesicle pool size was also reflected in a decrease in the frequency of 
      miniature synaptic currents. The progressive and gradual decline in vesicle 
      numbers and miniature event frequency we observed here may be an early indicator 
      of synapse degeneration, in keeping with observations during competitive 
      stimulation at the neuromuscular junction or age-related synapse elimination 
      recently reported by others. PPT1 did not colocalize with synaptic vesicle or 
      synapse markers, suggesting that lysosomal dysfunction leads indirectly to the 
      synaptic abnormalities. We conclude that from an early age, neurons deficient in 
      PPT1 enzyme activity display intrinsically abnormal properties that could 
      potentially explain key features of the clinical disease, such as myoclonus and 
      seizures.
FAU - Virmani, Tuhin
AU  - Virmani T
AD  - Center for Basic Neuroscience, University of Texas Southwestern Medical Center, 
      Dallas, TX 75390, USA.
FAU - Gupta, Praveena
AU  - Gupta P
FAU - Liu, Xinran
AU  - Liu X
FAU - Kavalali, Ege T
AU  - Kavalali ET
FAU - Hofmann, Sandra L
AU  - Hofmann SL
LA  - eng
GR  - MH068437/MH/NIMH NIH HHS/United States
GR  - NS36867/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Neurobiol Dis
JT  - Neurobiology of disease
JID - 9500169
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (palmitoyl-protein thioesterase)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Down-Regulation/genetics
MH  - Excitatory Postsynaptic Potentials/genetics
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Microscopy, Electron, Transmission
MH  - Nerve Degeneration/genetics/metabolism/physiopathology
MH  - Neuronal Ceroid-Lipofuscinoses/genetics/*metabolism/physiopathology
MH  - Presynaptic Terminals/*metabolism/pathology/ultrastructure
MH  - Synaptic Transmission/genetics
MH  - Synaptic Vesicles/*metabolism/pathology/ultrastructure
MH  - Thiolester Hydrolases/*genetics
EDAT- 2005/10/26 09:00
MHDA- 2006/01/24 09:00
CRDT- 2005/10/26 09:00
PHST- 2004/12/20 00:00 [received]
PHST- 2005/03/01 00:00 [revised]
PHST- 2005/03/03 00:00 [accepted]
PHST- 2005/10/26 09:00 [pubmed]
PHST- 2006/01/24 09:00 [medline]
PHST- 2005/10/26 09:00 [entrez]
AID - S0969-9961(05)00076-8 [pii]
AID - 10.1016/j.nbd.2005.03.012 [doi]
PST - ppublish
SO  - Neurobiol Dis. 2005 Nov;20(2):314-23. doi: 10.1016/j.nbd.2005.03.012.