The neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessively inherited diseases resulting in severe and progressive neurological disorders. Mutations in at least eight genes which encode proteins with known or unknown functions have been identified, however the neuropathogenic mechanisms remain still unclear. Retinal degeneration is a clue in many forms of NCLs, including a murine NCL model, the motor neuron degeneration (mnd) mouse bearing a mutation of CLN8 gene and representing the counterpart of CLN8 form in humans, the Northern Epilepsy. To gain insights into the mechanisms contributing to retinal degeneration in NCL, we here investigated the oxidative state and apoptotic cell death in retinas of mnd mouse and with regard to gender- and ageassociated differences. A progressive increase in oxyradicals and lipid peroxides as monitored by superoxide dismutase activity and TBARS levels was reported in retinas of female and male mnd mice. Female mnd retinas showed a higher oxidation and consistently exhibited prominent 4-hydroxy- 2-nonenal (4-HNE) -adducts staining in the inner plexiform and ganglion cell (GCL) layers, and an advanced histopathologic profile. TUNEL staining appeared in photoreceptor layer as early as 1 month of age, became more intense also in the inner nuclear layer (INL) and GCL at 4 months, and at 8 months, when complete loss of photoreceptors and atrophy of retinal layers had occurred, it was restricted to few nuclei in INL and GCL. Along with the morphological signs, activation caspase-3 was found and its processing turned out to be higher in females than males. Moreover, an increase in the expression of Bcl-xl appeared to be consistent with the slow and progressive nature of retinal cell demise. These results show involvement of oxidation and apoptotic processes in mnd mouse retinopathy and highlight for the first time sex-related differences in retinal vulnerability to oxidative stress and damage.
Retinal oxidation and apoptosis in the motor neuron degeneration mouse, a model of neuronal ceroid lipofuscinosis
Guarneri P;D'Agostino S;Russo D;Cascio C;
2004
Abstract
The neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessively inherited diseases resulting in severe and progressive neurological disorders. Mutations in at least eight genes which encode proteins with known or unknown functions have been identified, however the neuropathogenic mechanisms remain still unclear. Retinal degeneration is a clue in many forms of NCLs, including a murine NCL model, the motor neuron degeneration (mnd) mouse bearing a mutation of CLN8 gene and representing the counterpart of CLN8 form in humans, the Northern Epilepsy. To gain insights into the mechanisms contributing to retinal degeneration in NCL, we here investigated the oxidative state and apoptotic cell death in retinas of mnd mouse and with regard to gender- and ageassociated differences. A progressive increase in oxyradicals and lipid peroxides as monitored by superoxide dismutase activity and TBARS levels was reported in retinas of female and male mnd mice. Female mnd retinas showed a higher oxidation and consistently exhibited prominent 4-hydroxy- 2-nonenal (4-HNE) -adducts staining in the inner plexiform and ganglion cell (GCL) layers, and an advanced histopathologic profile. TUNEL staining appeared in photoreceptor layer as early as 1 month of age, became more intense also in the inner nuclear layer (INL) and GCL at 4 months, and at 8 months, when complete loss of photoreceptors and atrophy of retinal layers had occurred, it was restricted to few nuclei in INL and GCL. Along with the morphological signs, activation caspase-3 was found and its processing turned out to be higher in females than males. Moreover, an increase in the expression of Bcl-xl appeared to be consistent with the slow and progressive nature of retinal cell demise. These results show involvement of oxidation and apoptotic processes in mnd mouse retinopathy and highlight for the first time sex-related differences in retinal vulnerability to oxidative stress and damage.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
