Upregulation of Bcl-2 and Elevation of Ceramide in Batten Disease

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.

Regulating survival and development in the retina: key roles for simple sphingolipids

“…The earliest indirect evidence suggesting a role for Cer in retinal pathologies was the increased Cer levels in brains of patients with the juvenile form of Batten disease, in which neuronal apoptosis in the retina and brain leads to blindness and cognitive decline ( 139 ) and in retinas of patients with Farber disease, which is also associated with blindness ( 140, 141 ). Acharya et al ( 142 ) …”

A Galactosylceramide Binding Domain Is Involved in Trafficking of CLN3 from Golgi to Rafts via Recycling Endosomes

“…There is an increase in ceramide levels in CLN3-deficient brain and cells. Conversely, CLN3-overexpressing cells generated 70% less ceramide than did normal cells (12). An increase in ceramide generation was subsequently described in association with another neurodegenerative disease, amyotrophic lateral sclerosis (14,15).…”

“…Defects in the CLN3 protein lead to dysregulation of pH in both yeast and mammalian cells (5,6). Also, ample evidence exists that neuronal death in JNCL is the result of apoptosis (7)(8)(9)(10)(11)(12)(13). Inspection of the primary CLN3 sequence led us to identify two short segments, 291VYFAE295 and 330VFASRSSL337, that are highly conserved across species and necessary for the role of the CLN3 protein in regulating cell growth and apoptosis (11).…”

Induction of Apoptosis by 1,4-Benzothiazine Analogs in Mouse Thymocytes

“…Dysregulated PCD contributes to many pathologies, including tumor promotion, neurodegenerative disorders, and autoimmune and immunodeficiency diseases (France-Lanord et al, 1997;Puranam et al, 1997;Taniwaki et al, 1999;Krammer, 2000;Yuan and Yankner, 2000). Therefore, the identification of agents and stimuli able to induce apoptosis, and the definition of activated signaling pathways, are of enormous interest.…”

“…Most of those molecular events, including aSMase activation and ceramide generation, have been previously associated with other cell death systems including DEX or Fas-induced apoptosis (Cifone et al, 1999;Kroesen et al, 2001). Of interest, aSMase activation and ceramide generation have been shown to be involved in neurodegenerative diseases, such as Parkinson's Disease, in which a role of 1,4-B has been proposed (France-Lanord et al, 1997;Puranam et al, 1997;Ariga et al, 1998;Taniwaki et al, 1999;Yuan and Yankner, 2000).…”