Neurodegenerative diseases constitute a class of illnesses marked by pathological protein aggregation in the brains of affected individuals. Although these disorders are invariably characterized by the degeneration of highly specific subpopulations of neurons, protein aggregation occurs in all cells, which indicates that toxicity arises only in particular cell biological contexts. Aggregation-associated disorders are unified by a common cell biological feature: the deposition of the culprit proteins in inclusion bodies. The precise function of these inclusions remains unclear. The starting point for uncovering the origins of disease pathology must therefore be a thorough understanding of the general cell biological function of inclusions and their potential role in modulating the consequences of aggregation. Here, we show that in human cells certain aggregate inclusions are active compartments. We find that toxic aggregates localize to one of these compartments, the juxtanuclear quality control compartment (JUNQ), and interfere with its quality control function. The accumulation of SOD1G93A aggregates sequesters Hsp70, preventing the delivery of misfolded proteins to the proteasome. Preventing the accumulation of SOD1G93A in the JUNQ by enhancing its sequestration in an insoluble inclusion reduces the harmful effects of aggregation on cell viability. aggregation quality control | ALS | insoluble protein deposit | protein folding

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Obesity is a multigenic trait that is a major risk factor for a number of common diseases, particularly Type II (non-insulin-dependent) diabetes mellitus, cardiovascular disease and hypertension. A recent review reported a total of 44 genomic locations with possible linkage to one or more obesity-related phenotypes [1]. Because false positive findings are common in genome scans for complex traits, replication is essential before undertaking gene identification studies. Previously, linkages for obesity traits have been replicated in three regions, 2p21, 7q31, and 20q13 [1].To date one of the strongest findings of linkage was reported by French investigators, linking obesity (BMI ³ 27 kg/m 2 ) to markers in chromosome 10p12 [2]. Recently [3], these results were replicated in a cohort of German families. In our previous genome scan [4], we did not find significant linkage to this region, although we did find secondary linkages for centromeric and distal 10 q markers, corresponding to secondary peaks found in the French study for a leptin phenotype. Our genome scan had a relatively small sample size of only 92 families and we examined more extreme levels of obesity (BMI ³ 30 kg/m 2 and BMI ³ 40 kg/m 2 ) and we did not have dense marker coverage in the region of the French linkage finding.In the current analysis, we examined linkage in this region in cohorts of 170 European-American and 43 African-American families (including the 92 families from the original genome scan). AbstractAims/hypothesis. Obesity is a complex trait influenced by multiple genes. We evaluated linkage in three regions of human chromosome 10 previously linked to obesity-related phenotypes. Methods. We conducted non-parametric linkage analysis of obesity-related phenotypes in cohorts of 170 European-American and 43 African-American families having extremely obese and normal weight subjects.

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