👤 K L Puranam

During brain development, excess neurons that are formed die by apoptosis. cln3 was recently identified as the gene defective in juvenile Batten disease, an inherited neurodegenerative disease of childhood. In this disease, neurons die by apoptosis. Overexpression of this gene increases survival of human NT2 neuronal precursor cells. We, therefore, hypothesized that cln3 may be present in developing neurons and may play an important role in regulating the developmental process. NT2 neuronal cells were induced to develop into mature neurons. We evaluated cln3 expression by reverse transcription PCR and immunohistochemistry over a 7-wk period of differentiation. Also, cln3 expression was characterized in neonatal rat brain during the first week of life (P-1, P0, P4, and P8) and at P30. cln3 was differentially expressed during neuronal development into nondividing post-mitotic neurons. The greatest expression was noted during wk 6 and then dropped to predifferentiation levels during wk 7. cln3 expression was detected in all the rat brain developmental stages evaluated. The greatest expression was seen at P0 and was double compared with the other stages. We conclude that cln3 is present during critical periods of neuronal cell differentiation and brain development. As cln3 is antiapoptotic, we hypothesize that cln3 plays an important role in regulating brain development. These findings may have implications for identifying strategies aimed at neuroprotection and neuronal survival during development. Show less

Juvenile neuronal ceroid lipofuscinosis or Batten disease (JNCL) is a neurodegenerative disorder characterized by blindness, seizures, cognitive decline and early death. Brain atrophy and retinitis pigmentosa ensue because of neuronal and photoreceptor apoptosis. The CLN3 gene defective in JNCL encodes a novel 438 amino acid protein. Most affected genes harbor a deletion resulting in a truncated protein. CLN3 overexpression in NT2 cells enhances growth, reverses growth inhibition induced by serum starvation and protects from apoptosis induced by vincristine, staurosporine, and etoposide but not from death caused by ceramide. CLN3 modulates endogenous and vincristine-activated ceramide, and therefore suppresses apoptosis by impacting generation of ceramide. Show less

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. Show less