Linked Life Data

17314303

Source:http://linkedlifedata.com/resource/pubmed/id/17314303

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
8
pubmed:dateCreated
2007-2-22
pubmed:abstractText
Neuronal ceroid lipofuscinosces/Batten disease (NCL) is a devastating group of neurodegenerative diseases caused by genetic disruptions in lysosomal function. Cathepsin D (CD) is a major lysosomal protease, and mutations in CD that render it enzymatically defective have been reported recently in subsets of NCL patients. The targeted deletion of CD in mice results in extensive neuropathology, including biochemical and morphological evidence of apoptosis and autophagic stress (aberrant autophagosome accumulation), effects that are similar to those observed in NCL. To determine the contribution of Bax-dependent apoptosis in this mouse model of NCL, combined Bax- and CD-deficient mice were generated. Morphological analysis of CD-deficient mouse brains indicated large numbers of pyknotic neurons and neurons with marked cytoplasmic swellings containing undigested lipofuscin. Cell death and apoptosis were evidenced by increases in terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) reactivity and activation of caspase-3, respectively. DeOlmos silver-positive neurons were abundant in CD-deficient brain and correlated with neuron loss, as indicated by significant decreases in NeuN (neuronal nuclear antigen)-positive neurons. Lysosome dysfunction and autophagic stress were apparent in CD-deficient brain as indicated by the accumulation of autofluorescent storage material and by increased levels of LC3-II (light chain 3-II, a selective autophagosome marker), respectively. Bax deletion significantly inhibited caspase-3 activation and hippocampal TUNEL reactivity but did not prevent the majority of CD deficiency-induced neuropathology, including the persistence of pyknotic neurons, elevated cortical TUNEL reactivity, lysosome dysfunction and autophagic stress, neurodegeneration, and neuron loss. Together, these results suggest that CD deficiency-induced neuropathology does not require Bax-dependent apoptosis and highlights the importance of caspase-independent neuron death and neurodegeneration resulting from the genetic disruption of lysosome function.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1529-2401
pubmed:author
pubmed:issnType
Electronic
pubmed:day
21
pubmed:volume
27
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2081-90
pubmed:dateRevised
2007-12-3
pubmed:meshHeading
pubmed-meshheading:17314303-Animals, pubmed-meshheading:17314303-Apoptosis, pubmed-meshheading:17314303-Autophagy, pubmed-meshheading:17314303-Brain, pubmed-meshheading:17314303-Caspase 3, pubmed-meshheading:17314303-Cathepsin D, pubmed-meshheading:17314303-Cell Death, pubmed-meshheading:17314303-Disease Models, Animal, pubmed-meshheading:17314303-Enzyme Activation, pubmed-meshheading:17314303-Hippocampus, pubmed-meshheading:17314303-In Situ Nick-End Labeling, pubmed-meshheading:17314303-Lipofuscin, pubmed-meshheading:17314303-Lysosomes, pubmed-meshheading:17314303-Mice, pubmed-meshheading:17314303-Mice, Inbred C57BL, pubmed-meshheading:17314303-Mice, Knockout, pubmed-meshheading:17314303-Microtubule-Associated Proteins, pubmed-meshheading:17314303-Nerve Degeneration, pubmed-meshheading:17314303-Nerve Tissue Proteins, pubmed-meshheading:17314303-Neuronal Ceroid-Lipofuscinoses, pubmed-meshheading:17314303-Neurons, pubmed-meshheading:17314303-Nuclear Proteins, pubmed-meshheading:17314303-bcl-2-Associated X Protein
pubmed:year
2007
pubmed:articleTitle
Cathepsin D deficiency induces persistent neurodegeneration in the absence of Bax-dependent apoptosis.
pubmed:affiliation
Department of Pathology, Neuropathology Division, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural