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Upregulation of Bcl-2 and elevation of ceramide in Batten disease
K Puranam1, W H Qian, K Nikbakht
1Department of Pediatrics (Division of Pediatric Neurology), Duke University Medical Center, Durham, North Carolina, USA.
Abstract:
The late infantile and juvenile variants of Batten disease are genetically distinct neurodegenerative disorders. Hallmarks of Batten disease include cognitive and motor decline, seizures and blindness due to retinitis pigmentosa. Recently, the CLN3 gene responsible for the juvenile variant has been cloned. Also, apoptosis was proven to be the mechanism by which neurons and photoreceptors die. This paper provides mechanistic support for the occurrence of apoptosis in this disease: There was marked upregulation of Bcl-2 in brain from the late infantile and juvenile types at the protein and RNA levels both by immunocytochemistry and by Northern blot analysis; there were also a 42% to 197% increase in brain ceramide determinations in brains from three patients with the juvenile type and three patients with the late infantile type. Double immunolabeling of brain sections for apoptosis and Bcl-2 supported a protective role for Bcl-2 in the juvenile form of Batten disease. These results raise the possibility that the intact CLN3 gene is normally antiapoptotic, and that it could be an upstream regulator of ceramide.
Insights
Batten disease involves neurodegeneration, seizures, and blindness. This study found increased Bcl-2 and ceramide levels, suggesting the CLN3 gene may normally prevent cell death in juvenile Batten disease.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Batten disease comprises distinct neurodegenerative disorders affecting children.
- Key features include cognitive/motor decline, seizures, and blindness.
- Apoptosis (programmed cell death) is the established mechanism for neuronal and photoreceptor loss.
Purpose of the Study:
- To investigate the mechanistic role of apoptosis in late infantile and juvenile Batten disease.
- To explore the involvement of Bcl-2 and ceramide in the disease pathology.
- To elucidate the function of the CLN3 gene in neuronal survival.
Main Methods:
- Immunocytochemistry and Northern blot analysis to assess Bcl-2 protein and RNA levels in patient brain tissue.
- Ceramide level determination in brain samples from patients with both disease variants.
- Double immunolabeling to evaluate the relationship between apoptosis and Bcl-2 expression.
Main Results:
- Significant upregulation of Bcl-2 was observed at both protein and RNA levels in affected brain regions.
- Ceramide levels increased substantially (42%–197%) in brains from patients with both late infantile and juvenile Batten disease.
- Bcl-2 demonstrated a protective role in the juvenile form, as indicated by double immunolabeling.
Conclusions:
- The findings provide mechanistic support for apoptosis in Batten disease.
- Results suggest that the intact CLN3 gene possesses antiapoptotic functions.
- The CLN3 gene may act as an upstream regulator of ceramide metabolism.