SorCS1 and SorL1/SorLA/LR11 belong to the sortilin family of vacuolar protein sorting-10 (Vps10) domain-containing proteins. Both are genetically associated with Alzheimer's disease (AD), and SORL1 expression is decreased in the brains of patients suffering from AD. SORCS1 is also genetically associated with types 1 and 2 diabetes mellitus (T1DM, T2DM). We have undertaken a study of the possible role(s) for SorCS1 in metabolism of the Alzheimer's amyloid-␤ peptide (A␤) and the A␤ precursor protein (APP), to test the hypothesis that Sorcs1 deficiency might be a common genetic risk factor underlying the predisposition to AD that is associated with T2DM. Overexpression of SorCS1c␤-myc in cultured cells caused a reduction ( p ϭ 0.002) in A␤ generation. Conversely, endogenous murine A␤ 40 and A␤ 42 levels were increased (A␤ 40 , p ϭ 0.044; A␤ 42 ,pϭ0.007)inthebrainsoffemaleSorcs1hypomorphicmice,possiblyparallelingthesexualdimorphismthatischaracteristicofthegenetic associations of SORCS1 with AD and DM. Since SorL1 directly interacts with Vps35 to modulate APP metabolism, we investigated the possibility that SorCS1c␤-myc interacts with APP, SorL1, and/or Vps35. We readily recovered SorCS1:APP, SorCS1:SorL1, and SorCS1:Vps35 complexes from nontransgenic mouse brain. Notably, total Vps35 protein levels were decreased by 49% ( p ϭ 0.009) and total SorL1 protein levels were decreased by 29% ( p ϭ 0.003) in the brains of female Sorcs1 hypomorphic mice. From these data, we propose that dysfunction of SorCS1 may contribute to both the APP/A␤ disturbance underlying AD and the insulin/glucose disturbance underlying DM.

We previously mapped the type 2 diabetes mellitus-2 locus (T2dm2), which affects fasting insulin levels, to distal chromosome 19 in a leptin-deficient obese F2 intercross derived from C57BL/6 (B6) and BTBR T+ tf/J (BTBR) mice. Introgression of a 7-Mb segment of the B6 chromosome 19 into the BTBR background (strain 1339A) replicated the reduced insulin linked to T2dm2. The 1339A mice have markedly impaired insulin secretion in vivo and disrupted islet morphology. We used subcongenic strains derived from 1339A to localize the T2dm2 quantitative trait locus (QTL) to a 242-kb segment comprising the promoter, first exon and most of the first intron of the Sorcs1 gene. This was the only gene in the 1339A strain for which we detected amino acid substitutions and expression level differences between mice carrying B6 and BTBR alleles of this insert, thereby identifying variation within the Sorcs1 gene as underlying the phenotype associated with the T2dm2 locus. SorCS1 binds platelet-derived growth factor, a growth factor crucial for pericyte recruitment to the microvasculature, and may thus have a role in expanding or maintaining the islet vasculature. Our identification of the Sorcs1 gene provides insight into the pathway underlying the pathophysiology of obesity-induced type 2 diabetes mellitus.

The pathogenesis of type 2 diabetes is intimately intertwined with the vasculature. Insulin must efficiently enter the bloodstream from pancreatic beta-cells, circulate throughout the body, and efficiently exit the bloodstream to reach target tissues and mediate its effects. Defects in the vasculature of pancreatic islets can lead to diabetic phenotypes. Similarly, insulin resistance is accompanied by defects in the vasculature of skeletal muscle, which ultimately reduce the ability of insulin and nutrients to reach myocytes. An underappreciated participant in these processes is the vascular pericyte. Pericytes, the smooth muscle-like cells lining the outsides of blood vessels throughout the body, have not been directly implicated in insulin secretion or peripheral insulin delivery. Here, we review the role of the vasculature in insulin secretion, islet function, and peripheral insulin delivery, and highlight a potential role for the vascular pericyte in these processes.

The vacuolar membrane ATPase (V-ATPase) is a protein complex that utilizes ATP hydrolysis to drive protons from the cytosol into the vacuolar lumen, acidifying the vacuole and modulating several key cellular response systems in Saccharomyces cerevisiae. To study the contribution of V-ATPase to the biology and virulence attributes of the opportunistic fungal pathogen Candida albicans, we created a conditional mutant in which VMA3 was placed under the control of a tetracycline-regulated promoter (tetR-VMA3 strain). Repression of VMA3 in the tetR-VMA3 strain prevents V-ATPase assembly at the vacuolar membrane and reduces concanamycin A-sensitive ATPase-specific activity and proton transport by more than 90%. Loss of C. albicans VATPase activity alkalinizes the vacuolar lumen and has pleiotropic effects, including pH-dependent growth, calcium sensitivity, and cold sensitivity. Candida albicans is a major opportunistic human fungal pathogen and is responsible for 6.8% of hospital-acquired infections in the United States (1). Despite the availability of several classes of antifungal drugs, attributable mortality, cost of care, and length of stay due to invasive candidiasis remain unacceptably high (2, 3). In addition, resistance to currently available antifungal drugs is emerging (see reference 4 for a review). Therefore, development of new antifungal drug targets remains a critical need. A diverse set of factors contributing to C. albicans virulence have been identified, including the secretion of aspartyl proteases and lipases, filamentation, and biofilm formation (5-8). Understanding the biology and regulation of these processes and pathways may illuminate new candidates for antifungal therapy.The vacuole is a dynamic acidic organelle found in yeast and plants that is analogous to the mammalian lysosome. It functions in an array of cellular homeostasis processes and thereby plays an important role in stress response, adaptation to novel environments, and cell differentiation (9-13). Furthermore, in C. albicans, intact vacuolar function is important for filamentation and virulence (12)(13)(14)(15). Vacuolar function depends on the maintenance of acidic pH by the vacuolar H-ATPase (V-ATPase), an enzyme complex that functions in organelle acidification across eukaryotes (16,17). The V-ATPase utilizes hydrolysis of ATP to transport protons from the cytosol into a variety of organelles. V-ATPase-mediated acidification and membrane energization are necessary for important vacuolar functions, including calcium and metal homeostasis (18), cargo sorting and membrane trafficking in endocytic and secretory pathways (19), and drug resistance (20). In Saccharomyces cerevisiae, the V-ATPase is expressed at the vacuolar membrane and the membrane of prevacuolar compartments and the Golgi compartment.The V-ATPase complex consists of the V 1 and V o subcomplexes (16). The V 1 subcomplex is composed of peripherally associated subunits that form the sites of ATP binding and hydrolysis on the cytosolic side of the membrane. The V o su...

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