Summary Disruption of the TRPML1 channel results in the neurodegenerative disorder mucolipidosis type IV (MLIV), a lysosomal storage disease with severe motor impairments. The mechanisms underlying MLIV are poorly understood and there is no treatment. Here, we report a Drosophila MLIV model, which recapitulates the key disease features, including abnormal intracellular accumulation of macromolecules, motor defects and neurodegeneration. The basis for the buildup of macromolecules was defective autophagy, which resulted in oxidative stress and impaired synaptic transmission. Late-apoptotic cells accumulated in trpml mutant brains suggesting diminished cell clearance. The accumulation of late apoptotic cells and motor deficits were suppressed by expression of trpml+ in neurons, glia or hematopoietic cells. We conclude that the neurodegeneration and motor defects result primarily from decreased clearance of apoptotic cells. Since hematopoietic cells in humans are involved in clearance of apoptotic cells, our results raise the possibility that bone marrow transplantation may limit the progression of MLIV.

We tested the hypothesis that concentrations of adipocytokines are altered in SLE and associated with coronary atherosclerosis, insulin resistance and inflammation. Concentrations of resistin, leptin, adiponectin, and visfatin were measured in 109 patients with SLE and in 78 control subjects. Coronary calcification was measured by electron beam computed tomography and insulin resistance was defined by the homeostasis (HOMA) index. Concentrations of adiponectin (28.7+/−17.9 vs. 22.0 +/−15.3 µg/mL, p=0.003), leptin (41.1+/−49.9 vs. 19.8+/−24.6 ng/mL, p<0.001) and visfatin (7.5+/ −10.5 vs. 4.5+/−2.8 ng/mL, p<0.001) were higher in patients with SLE than controls. These differences remained significant after adjustment for age, race, sex and BMI, (all p-values<0.02). Concentrations of resistin (10.7+/−7.6 vs. 9.1+/−5.1 ng/mL, p=0.41) did not differ in patients and controls. In patients with SLE, leptin was positively associated with BMI (rho=0.80, p<0.001), insulin resistance (rho=0.46, p<0.001), and CRP (rho=0.30, p=0.002), while adiponectin was negatively associated with the same factors (rho= −0.40, p<0.001; rho= −0.38, p<0.001, rho=− 0.22, p=0.02, respectively). None of the adipocytokines were associated with coronary atherosclerosis in SLE. In conclusion, patients with SLE have increased concentrations of adiponectin, leptin and visfatin. Lower concentrations of adiponectin and higher concentrations of leptin are associated with insulin resistance, BMI and CRP in patients with SLE. Keywordssystemic lupus erythematosus; adipocytokines; atherosclerosis; insulin resistance; inflammation Adipose tissue has endocrine functions and is the main source of several mediators, termed adipocytokines, which include leptin, resistin, visfatin and adiponectin. These adipocytokines have profound effects on glucose homeostasis, appetite regulation, inflammation and atherosclerosis. 1 Leptin, resistin and visfatin have pro-inflammatory and atherogenic effects and are associated with insulin resistance. 1, 2 For example, increased concentrations of these three adipocytokines are found in animal models of obesity and in individuals with diabetes, 1 and higher Thus, adipocytokines may provide a mechanistic link between impaired insulin sensitivity, obesity, chronic inflammation, and atherosclerosis. We have reported that patients with systemic lupus erythematosus (SLE) frequently meet the criteria for the metabolic syndrome 7 , and have accelerated atherosclerosis 8 and a higher prevalence of insulin resistance. 7 Little is known about adipocytokines in SLE. 9 We therefore examined the hypothesis that concentrations of adipocytokines are altered in SLE and associated with coronary atherosclerosis, insulin resistance and inflammation. MethodsWe studied 109 patients with SLE and 78 control subjects who are participating in ongoing clinical investigations into the prevalence and mechanisms of atherosclerosis. 7, 8, 10-12 Eligible SLE patients included individuals who met the criteria for SLE, 13 were over 18 years of age, and h...

Inhibition of Cdc42 by dRich induces postsynaptic release of the BMP ligand Glass bottom boat.