Dégénérescence maculaire liée à l'âge

La dégénérescence maculaire liée à l'âge (DMLA) ou dégénérescence maculaire sénile est une maladie de la rétine provoquée par une dégénérescence progressive de la macula, partie centrale de la rétine, qui peut apparaître à partir de l'âge de , et plus fréquemment à partir de , provoquant un affaiblissement important des capacités visuelles, sans toutefois les anéantir. C'est la première cause de malvoyance après dans les pays développés. Bien que certaines dystrophies affectent les personnes plus jeunes, on maintient le terme DMLA. Les causes précises de cette maladie restent inconnues ; la maladie est probablement polygénique et multifactorielle, avec des facteurs génétiques de susceptibilité (« prédisposants ») et d'autres facteurs, au contraire, « protecteurs ». La rétine est un réseau de récepteurs visuels et de nerfs. Il se trouve sur la choroïde, un réseau de vaisseaux sanguins alimentant la rétine avec le sang. Dans la form

Analysis of the Cytoprotective Role of alpha-Crystallins in Cell Survival and Implication of the alpha A-Crystallin C-Terminal Extension Domain in Preventing Bax-Induced Apoptosis

Séverine Hamann

alpha-Crystallins, initially described as the major structural proteins of the lens, belong to the small heat shock protein family. Apart from their function as chaperones, alpha-crystallins are involved in the regulation of intracellular apoptotic signals. alpha A- and alpha B-crystallins have been shown to interfere with the mitochondrial apoptotic pathway triggering Bax pro-apoptotic activity and downstream activation of effector caspases. Differential regulation of alpha-crystallins has been observed in several eye diseases such as age-related macular degeneration and stress-induced and inherited retinal degenerations. Although the function of alpha-crystallins in healthy and diseased retina remains poorly understood, their altered expression in pathological conditions argue in favor of a role in cellular defensive response. In the Rpe65(-/-) mouse model of Leber's congenital amaurosis, we previously observed decreased expression of alpha A- and alpha B-crystallins during disease progression, which was correlated with Bax pro-death activity and photoreceptor apoptosis. In the present study, we demonstrated that alpha-crystallins interacted with pro-apoptotic Bax and displayed cytoprotective action against Bax-triggered apoptosis, as assessed by TUNEL and caspase assays. We further observed in staurosporine-treated photoreceptor-like 661W cells stably overexpressing alpha A- or alpha B-crystallin that Bax-dependent apoptosis and caspase activation were inhibited. Finally, we reported that the C-terminal extension domain of alpha A- crystallin was sufficient to provide protection against Bax-triggered apoptosis. Altogether, these data suggest that alpha-crystallins interfere with Bax-induced apoptosis in several cell types, including the cone-derived 661W cells. They further suggest that alpha A-crystallin-derived peptides might be sufficient to promote cytoprotective action in response to apoptotic cell death.

Public Library of Science2013

Bax-Induced Apoptosis in Leber's Congenital Amaurosis: A Dual Role in Rod and Cone Degeneration

Séverine Hamann

Pathogenesis in the Rpe65(-/-) mouse model of Leber's congenital amaurosis (LCA) is characterized by a slow and progressive degeneration of the rod photoreceptors. On the opposite, cones degenerate rapidly at early ages. Retinal degeneration in Rpe65(-/-) mice, showing a null mutation in the gene encoding the retinal pigment epithelium 65-kDa protein (Rpe65), was previously reported to depend on continuous activation of a residual transduction cascade by unliganded opsin. However, the mechanisms of apoptotic signals triggered by abnormal phototransduction remain elusive. We previously reported that activation of a Bcl-2-dependent pathway was associated with apoptosis of rod photoreceptors in Rpe65(-/-) mice during the course of the disease. In this study we first assessed whether activation of Bcl-2-mediated apoptotic pathway was dependent on constitutive activation of the visual cascade through opsin apoprotein. We then challenged the direct role of pro-apoptotic Bax protein in triggering apoptosis of rod and cone photoreceptors. Quantitative PCR analysis showed that increased expression of pro-apoptotic Bax and decreased level of anti-apoptotic Bcl-2 were restored in Rpe65(-/-)/Gnat1(-/-) mice lacking the Gnat1 gene encoding rod transducin. Moreover, photoreceptor apoptosis was prevented as assessed by TUNEL assay. These data indicate that abnormal activity of opsin apoprotein induces retinal cell apoptosis through the Bcl-2-mediated pathway. Following immunohistological and real-time PCR analyses, we further observed that decreased expression of rod genes in Rpe65-deficient mice was rescued in Rpe65(-/-)/ Bax(-/-) mice. Histological and TUNEL studies confirmed that rod cell demise and apoptosis in diseased Rpe65(-/-) mice were dependent on Bax-induced pathway. Surprisingly, early loss of cones was not prevented in Rpe65(-/-)/Bax(-/-) mice, indicating that proapoptotic Bax was not involved in the pathogenesis of cone cell death in Rpe65-deficient mice. This is the first report, to our knowledge, that a single genetic mutation can trigger two independent apoptotic pathways in rod and cone photoreceptors in Rpe65-dependent LCA disease. These results highlight the necessity to investigate and understand the specific death signaling pathways committed in rods and cones to develop effective therapeutic approaches to treat RP diseases.

Public Library of Science2009

Analysis of the Cytoprotective Role of alpha-Crystallins in Cell Survival and Implication of the alpha A-Crystallin C-Terminal Extension Domain in Preventing Bax-Induced Apoptosis

Séverine Hamann

Public Library of Science2013

Bax-Induced Apoptosis in Leber's Congenital Amaurosis: A Dual Role in Rod and Cone Degeneration

Séverine Hamann

Public Library of Science2009