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Recessive mutations in DNAJC3, an endoplasmic reticulum (ER)-resident BiP co-chaperone, have been identified in patients with multisystemic neurodegeneration and diabetes mellitus. To further unravel these pathomechanisms, we employed a non-biased proteomic approach and identified dysregulation of several key cellular pathways, suggesting a pathophysiological interplay of perturbed lipid metabolism, mitochondrial bioenergetics, ER-Golgi function, and amyloid-beta processing. Further functional investigations in fibroblasts of patients with DNAJC3 mutations detected cellular accumulation of lipids and an increased sensitivity to cholesterol stress, which led to activation of the unfolded protein response (UPR), alterations of the ER-Golgi machinery, and a defect of amyloid precursor protein. In line with the results of previous studies, we describe here alterations in mitochondrial morphology and function, as a major contributor to the DNAJC3 pathophysiology. Hence, we propose that the loss of DNAJC3 affects lipid/cholesterol homeostasis, leading to UPR activation, β-amyloid accumulation, and impairment of mitochondrial oxidative phosphorylation.

The effect of dietary supplementation with Oil sardine ( Sardinella longiceps) fish at 2/3 fat replacement, on serum lipids in the cholesterol-stressed copper loaded rats was studied. Hypercholesterolemic state observed during copper toxicity was not alleviated by sardines. Copper loading significantly decreased the triglyceride levels and the activity of β-hydroxy β-methyl glutaryl (HMG) CoA reductase. Fish supplementation was further effective in reducing the triglyceride levels in copper loaded rats. Significant increase in the serum phospholipid was observed in the fish supplemented rats during copper overload. The finding suggests that hypolipidemic potential of fish is certainly altered to some extent in copper toxicity since, it is well known that copper enhances the formation of free radicals. Thus it may be concluded that sardine fish is not effective in reducing the cholesterol levels during copper toxicity. [ABSTRACT FROM AUTHOR]