Tion. Reduced endocytosis from the basal border could lead to exaggerated basal infoldings and reduced lysosomal delivery of ECM. Defective lysosomal function (lysosomal storage diseases) and endocytic function (neurodegenerative diseases) are 22948146 frequently associated 
with extracellular deposit formation (eg. amyloid plaques) and mice that express a mutant form of cathepsin D develop BlamDs [23]. Components of exosomes, lysosomes and autophagosomes have all been found in basal deposits, suggesting that HIV-RT inhibitor 1 manufacturer secretion of undigested material may contribute to deposit formation [25]. It is also possible that secretion of factors from uveal melanocytes in the ChmFlox, Tyr-Cre+ is impaired and this may affect thickening of BrM. The ashen mouse has not been reported to prematurely develop extracellular deposits, suggesting that their formation in the CHM mouse is not due to poorly prenylated Rab27a and is likely to be the result of other or multiple Rab dysfunction. Together, these data suggest a relationship between defective degradative capacity inside the cell and accumulation of deposits outside the cell.been observed in normal young eyes and do not necessarily lead to neovascularisation [27], but their increased presence in 
the ChmFlox, Tyr-Cre+ mice suggests some changes in the choroidal vasculature. Mouse buy Linolenic acid methyl ester transgenic models of AMD that form basal deposits include those caused by deletion/mutation of inflammatory genes (eg CFH, Ccr2, Ccl2), of genes related to oxidative stress (SOD2), metabolic pathway genes (ApoE, ApoB100) and intracellular proteases (cathepsin D, nephrilysin) [28]. Of these, the protease mutations have a clear direct link to deposit formation in that cathepsin D is important for the degradation of POS whilst nephrilysin is important for the degradation of beta amyloid, a component of drusen/basal deposits. Our mouse model thus contrasts with most existing models because the gene defect causes dysfunction of processes that could be primary causes of deposit formation ie defects in intra or extracellular degradation and secretion. Remarkably, very little attention has been paid to the role of membrane traffic in the formation of basal deposits. Although loss of Rep1 in the RPE is sufficient to increase the frequency of basal deposit formation and some changes in visual function [9] it is not sufficient to induce photoreceptor degeneration, as the neural retina is morphologically normal in the ChmFlox, Tyr-Cre+ mice. In addition we haven’t observed obvious changes in the choroid of the ChmFlox, Tyr-Cre+ mouse, suggesting that the absence of REP1 in the RPE and uveal melanocytes does not have a major impact on the choroid, at least in the life span of a mouse. Similarly we cannot exclude the possibility that the loss of REP1 in uveal melanocytes might contribute to the RPE pathology in ChmFlox, Tyr-Cre+ mice. We previously showed that loss of Rep1 in the photoreceptors and the RPE caused a more rapid degeneration of photoreceptors than loss of Rep1 in photoreceptors alone [9], suggesting that chronic membrane traffic defects in the RPE can make the photoreceptors more susceptible to other insults. The similarity between the phenotype of the ChmFlox, Tyr-Cre+ mice and changes associated with aging and early AMD pathogenesis suggest that these mice may allow the identification of trafficking pathways involved in these pathological changes.Supporting InformationFigure S1 Pigmentation of uveal melanocytes in ChmFlox, Tyr-Cre+ mouse. E.Tion. Reduced endocytosis from the basal border could lead to exaggerated basal infoldings and reduced lysosomal delivery of ECM. Defective lysosomal function (lysosomal storage diseases) and endocytic function (neurodegenerative diseases) are 22948146 frequently associated with extracellular deposit formation (eg. amyloid plaques) and mice that express a mutant form of cathepsin D develop BlamDs [23]. Components of exosomes, lysosomes and autophagosomes have all been found in basal deposits, suggesting that secretion of undigested material may contribute to deposit formation [25]. It is also possible that secretion of factors from uveal melanocytes in the ChmFlox, Tyr-Cre+ is impaired and this may affect thickening of BrM. The ashen mouse has not been reported to prematurely develop extracellular deposits, suggesting that their formation in the CHM mouse is not due to poorly prenylated Rab27a and is likely to be the result of other or multiple Rab dysfunction. Together, these data suggest a relationship between defective degradative capacity inside the cell and accumulation of deposits outside the cell.been observed in normal young eyes and do not necessarily lead to neovascularisation [27], but their increased presence in the ChmFlox, Tyr-Cre+ mice suggests some changes in the choroidal vasculature. Mouse transgenic models of AMD that form basal deposits include those caused by deletion/mutation of inflammatory genes (eg CFH, Ccr2, Ccl2), of genes related to oxidative stress (SOD2), metabolic pathway genes (ApoE, ApoB100) and intracellular proteases (cathepsin D, nephrilysin) [28]. Of these, the protease mutations have a clear direct link to deposit formation in that cathepsin D is important for the degradation of POS whilst nephrilysin is important for the degradation of beta amyloid, a component of drusen/basal deposits. Our mouse model thus contrasts with most existing models because the gene defect causes dysfunction of processes that could be primary causes of deposit formation ie defects in intra or extracellular degradation and secretion. Remarkably, very little attention has been paid to the role of membrane traffic in the formation of basal deposits. Although loss of Rep1 in the RPE is sufficient to increase the frequency of basal deposit formation and some changes in visual function [9] it is not sufficient to induce photoreceptor degeneration, as the neural retina is morphologically normal in the ChmFlox, Tyr-Cre+ mice. In addition we haven’t observed obvious changes in the choroid of the ChmFlox, Tyr-Cre+ mouse, suggesting that the absence of REP1 in the RPE and uveal melanocytes does not have a major impact on the choroid, at least in the life span of a mouse. Similarly we cannot exclude the possibility that the loss of REP1 in uveal melanocytes might contribute to the RPE pathology in ChmFlox, Tyr-Cre+ mice. We previously showed that loss of Rep1 in the photoreceptors and the RPE caused a more rapid degeneration of photoreceptors than loss of Rep1 in photoreceptors alone [9], suggesting that chronic membrane traffic defects in the RPE can make the photoreceptors more susceptible to other insults. The similarity between the phenotype of the ChmFlox, Tyr-Cre+ mice and changes associated with aging and early AMD pathogenesis suggest that these mice may allow the identification of trafficking pathways involved in these pathological changes.Supporting InformationFigure S1 Pigmentation of uveal melanocytes in ChmFlox, Tyr-Cre+ mouse. E.
