Purpose: Retinitis pigmentosa (RP) is a genetic degenerative disease causing blindness in later life. Several genes have been linked to this hereditary disease. While heterogeneity of such magnitude in RP would appear to represent a major impediment to the development of therapeutics, mutation-independent approaches to target common molecular mechanisms activated during the degenerative process have to be exploited. We molecularly characterized mitochondrial and ER pathways activated during rod cell death in three murine models of RP and developed molecules to interfere with their function. Methods: We studied the rd1, the Rho-/- and the P23H transgenic mouse models with immunocytochemical and biochemical approaches. We analyzed mitochondrial Aif, caspase-3 and caspase-7, Bax and Bak, calpain and cathepsin activation, ER caspase-12, and ER stress markers. We performed in vitro interferences with shRNAs and in vivo treatments with Calpain and Bax inhibiting substances. Results: We found that calpains play a key role in the activation of Aif, Bax and cell death in the rd1 retina. shRNA experiments down-regulating either calpain 1 or calpain 2 allowed to define the different contributions of these two proteases. By reduction of Aif expression we confirmed the important role of Aif in apoptosis in the rd1 retina. Aif appears also to be important in the other forms of retinal degeneration. Otherwise, only two ER stress pathways are activated in the degenerating rd1 retina and they appear not to be critical for cell death. Conclusions: The option of exploiting cell death as a therapeutic target is complex. Nevertheless the molecular understanding of the factors activated during degeneration and the identification of common activators are the first step toward this goal. Our study identifies calpains and Aif as a key factors triggering photoreceptor cell demise in the rd1 retina. The efficacy of interfering molecules targeting the different factors activated during the apoptotic cascade opens new perspectives for designing therapeutic approaches to rescue photoreceptor cell death in this disease.

Mitochondrial and ER pathways interplay in rod photoreceptor cell death / Marigo, Valeria; Comitato, Antonella; Morandi, Paolo; Benassi, Silvia. - STAMPA. - (2011), pp. 42-42. ((Intervento presentato al convegno ARVO/ISOCB 2011 Meeting tenutosi a Vancouver, Canada nel 7-10 Settembre 2011.

Mitochondrial and ER pathways interplay in rod photoreceptor cell death

MARIGO, Valeria;Comitato, Antonella;MORANDI, PAOLO;BENASSI, SILVIA
2011

Abstract

Purpose: Retinitis pigmentosa (RP) is a genetic degenerative disease causing blindness in later life. Several genes have been linked to this hereditary disease. While heterogeneity of such magnitude in RP would appear to represent a major impediment to the development of therapeutics, mutation-independent approaches to target common molecular mechanisms activated during the degenerative process have to be exploited. We molecularly characterized mitochondrial and ER pathways activated during rod cell death in three murine models of RP and developed molecules to interfere with their function. Methods: We studied the rd1, the Rho-/- and the P23H transgenic mouse models with immunocytochemical and biochemical approaches. We analyzed mitochondrial Aif, caspase-3 and caspase-7, Bax and Bak, calpain and cathepsin activation, ER caspase-12, and ER stress markers. We performed in vitro interferences with shRNAs and in vivo treatments with Calpain and Bax inhibiting substances. Results: We found that calpains play a key role in the activation of Aif, Bax and cell death in the rd1 retina. shRNA experiments down-regulating either calpain 1 or calpain 2 allowed to define the different contributions of these two proteases. By reduction of Aif expression we confirmed the important role of Aif in apoptosis in the rd1 retina. Aif appears also to be important in the other forms of retinal degeneration. Otherwise, only two ER stress pathways are activated in the degenerating rd1 retina and they appear not to be critical for cell death. Conclusions: The option of exploiting cell death as a therapeutic target is complex. Nevertheless the molecular understanding of the factors activated during degeneration and the identification of common activators are the first step toward this goal. Our study identifies calpains and Aif as a key factors triggering photoreceptor cell demise in the rd1 retina. The efficacy of interfering molecules targeting the different factors activated during the apoptotic cascade opens new perspectives for designing therapeutic approaches to rescue photoreceptor cell death in this disease.
ARVO/ISOCB 2011 Meeting
Vancouver, Canada
7-10 Settembre 2011
42
42
Marigo, Valeria; Comitato, Antonella; Morandi, Paolo; Benassi, Silvia
Mitochondrial and ER pathways interplay in rod photoreceptor cell death / Marigo, Valeria; Comitato, Antonella; Morandi, Paolo; Benassi, Silvia. - STAMPA. - (2011), pp. 42-42. ((Intervento presentato al convegno ARVO/ISOCB 2011 Meeting tenutosi a Vancouver, Canada nel 7-10 Settembre 2011.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1063566
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