Abstract
BackgroundAn arg120gly (R120G) missense mutation in HSPB5 (α-β-crystallin ), which belongs to the small heat shock protein (HSP) family, causes desmin-related cardiomyopathy (DRM), a muscle disease that is characterized by the formation of inclusion bodies, which can contain pre-amyloid oligomer intermediates (amyloid oligomer). While we have shown that small HSPs can directly interrupt amyloid oligomer formation, the in vivo protective effects of the small HSPs on the development of DRM is still uncertain.Methodology/Principal FindingsIn order to extend the previous in vitro findings to in vivo, we used geranylgeranylacetone (GGA), a potent HSP inducer. Oral administration of GGA resulted not only in up-regulation of the expression level of HSPB8 and HSPB1 in the heart of HSPB5 R120G transgenic (R120G TG) mice, but also reduced amyloid oligomer levels and aggregates. Furthermore, R120G TG mice treated with GGA exhibited decreased heart size and less interstitial fibrosis, as well as improved cardiac function and survival compared to untreated R120G TG mice. To address possible mechanism(s) for these beneficial effects, cardiac-specific transgenic mice expressing HSPB8 were generated. Overexpression of HSPB8 led to a reduction in amyloid oligomer and aggregate formation, resulting in improved cardiac function and survival. Treatment with GGA as well as the overexpression of HSPB8 also inhibited cytochrome c release from mitochondria, activation of caspase-3 and TUNEL-positive cardiomyocyte death in the R120G TG mice.Conclusions/SignificanceExpression of small HSPs such as HSPB8 and HSPB1 by GGA may be a new therapeutic strategy for patients with DRM.
Highlights
Many systemic and neurodegenerative disorders whose etiologies are linked to misfolded or unfolded proteins are characterized by the accumulation of intracellular or extracellular protein deposits or aggregates known as aggresomes [1,2]
While we have shown that HSPB1 and HSPB8 can directly interrupt amyloid oligomer formation caused by HSPB5 R120G and restore cellular viability in cardiomyocytes expressing HSPB5 R120G, the in vivo protective effects of the small heat shock protein (HSP) on the development of desmin-related cardiomyopathy (DRM) remain unproven
Since we have found that HSPB8 and HSPB1 can reduce the amyloid oligomer toxicity generated by HSPB5 R120G [15], we analyzed the effect of GGA on generating amyloid oligomers caused by HSPB5 R120G expression (Figure 1C and D)
Summary
Many systemic and neurodegenerative disorders whose etiologies are linked to misfolded or unfolded proteins are characterized by the accumulation of intracellular or extracellular protein deposits or aggregates known as aggresomes [1,2]. It is known that mutations or other changes in the chaperone proteins themselves cause them to promote misfolding, rather than guard against it [9]. This implies that cellular levels of HSPs play a critical role in progression and severity of disease linked to misfolded or unfolded proteins. An arg120gly (R120G) missense mutation in HSPB5 (a-b-crystallin ), which belongs to the small heat shock protein (HSP) family, causes desmin-related cardiomyopathy (DRM), a muscle disease that is characterized by the formation of inclusion bodies, which can contain pre-amyloid oligomer intermediates (amyloid oligomer). While we have shown that small HSPs can directly interrupt amyloid oligomer formation, the in vivo protective effects of the small HSPs on the development of DRM is still uncertain
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