In cultured cells, heat shock and drug treatment induce collapse of IFs and associated Hsp27 and aBcrystallin, demonstrating that these small heat shock proteins are not sufficient topreventfilament collapse, and suggesting thatthepurpose of this association is more than just structural. Inclusion of aBcrystallin prevents IF gel formation in vitro but not filament assembly, suggesting that one of the major functions of the association of small heat shock proteins with IFs is to help regulate the interactions that occur between filaments in their cellular networks. Investigators have suggested that aB-crystallin does not alter the polymerization state of IF proteins in primary astrocytes, but ectopic expression of aB-crystallin in the absence of stress can modify the organizational state of IF and aB-crystallin can function as an IF debundling protein. The sequence and structural domains that mediate aB-crystallin interactions with IFs include peptide residues 113�C120, the region in the C-terminal domain of human aB-crystallin that includes the aBR120G that causes human hereditary Folinic acid calcium salt pentahydrate cataracts and myopathy, suggesting dysregulation of IFs may contribute to hereditary cataracts and DRM. Wild-type aB-crystallin plays a beneficial role in the formation of desmin filament networks in muscle. In humans, and perhaps also in mice, the promotion of desmin filament aggregation by aB-R120G mutant protein may be repressed at a young age by the expression of competing wild-type aB-crystallin, which could explain the late onset of myopathies caused by aBcrystallin mutations. The results of the present study indicate that the mutant aB-R120G protein exhibits a gain of toxic function that explains the autosomal dominant nature of the aB-R120G-associated cataracts and myopathic disease. Desmin-related Chlorhexidine hydrochloride cardiomyopathy has been recapitulated in transgenic mice by cardiac-specific expression of the aB-R120G protein. These mice develop severe cardiomyopathy with early death at 28 weeks in a gene dosage-dependent manner. We did not observe a similar elevated mortality in aB-R120G crystallin knock-in mice. This may be because of expression of aB-R120G crystallin at endogenous levels, whereas previous studies have overexpressed aB-R120G crystallin in the target tissue. Cardiac chaperone dysfunction perturbs cardiac mitochondrial architecture and impairs mitochondrial function. These changes ultimately lead to cardiomyocyte death, dilation, and heart failure. In another study, increased glucose-6-phosphate dehydrogenase expression was sufficient to cause cardiomyopathy in transgenic mice, which may be an additional mechanism underlying aB-R120G-associated cardiomyopathy. Other in vitro studies have suggested that the intracellular aggregation of desmin and mutant aB-R120G in DRM may be caused by impaired aB-crystallin function and loss of its native supramolec ular organization. Investigators have also suggested that wildtype aB-crystallin might co-oligomerize with aB-R120G and prevent the formation of aggresomes. Other chaperones such as 
HSP70 or HSPB8 have also been shown to reduce the frequency of aggregate formation in vitro. Although the molecular basis of cataract and DRM development is not fully understood, the aB-R120G knock-in mice are a useful model for identifying the effects of molecular mechanisms that affect intermediate filament aggregation and lead to cataract formation and DRM. In summary, we have generated a knock-in aB-R120G mouse model to study the mechanisms of human hereditary cataract development and have demonstrated that these animals begin to develop cataracts and muscle dysfunction at a young age. This multi-system model recapitulates many features of human hereditary cataracts and DRM. We have shown that the lens and muscle pathologies share many features, including increased insolubility of aB-crystallin with gene dosage, and increased co-aggregation of aBcrystallin with intermediate filament proteins.