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Endoplasmic Reticulum Stress‐Mediated Caspase‐4 Activation and Apoptosis Lead to Neurodegeneration in INCL
Author(s) -
Kim SungJo,
Zhang Zhongjian,
Hitomi Emiko,
Mukherjee Anil B
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a506-a
Subject(s) - endoplasmic reticulum , neurodegeneration , microbiology and biotechnology , apoptosis , unfolded protein response , chemistry , biology , biochemistry , medicine , disease
Infantile Neuronal Ceroid Lipofuscinosis (INCL), commonly known as infantile Batten disease, is a rare, uniformly fatal, progressive encephalopathy of children. Inactivating mutations in the gene encoding palmitoyl‐protein thioesterase‐1 (PPT1) is the molecular basis of INCL. PPT1 is a lysosomal enzyme that cleaves thioester linkages in s‐acylated proteins. Due to the lack of PPT1 enzymatic activity, the palmitic acid linked to these proteins is not removed and as a result, the lipid‐modified proteins are not degraded or recycled. Although apoptosis is the suggested cause of neuronal death in INCL neither the molecular mechanisms of apoptosis nor the reasons for rapid brain atrophy are defined. Understanding the molecular mechanisms of neuronal apoptosis would facilitate the development of therapeutic approaches to this disease. Using cultured cells and autopsy brain samples from INCL patients, we discovered that these cells undergo endoplasmic reticulum (ER) stress attested by the expression of canonical ER‐stress marker protein, Grp‐78, at a high level. To confirm these results we induced the expression of GFP‐tagged GAP‐43, a palmitoylated protein in INCL and normal cells to determine the cellular localization of this protein. We found that while GFP‐GAP‐43 is diffusely distributed in normal cells, it is abnormally accumulated in the ER‐Golgi region of the INCL cells. We also found that in INCL cells ER stress mediates activation of caspase‐4, which leads to caspase‐3 activation and apoptosis. Most importantly, we found that inhibition of caspase‐4 activity by a specific inhibitor of this enzyme protects the INCL cells from apoptosis. Our results, for the first time, define a major pathway to apoptosis in INCL providing insight into the pathogenesis of this disease and identify potential targets for therapeutic intervention.