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Barcoding heat shock proteins to human diseases: looking beyond the heat shock response.

Kakkar V, Meister-Broekema M, Minoia M, Carra S, Kampinga HH - Dis Model Mech (2014)

Bottom Line: There are numerous human diseases that are associated with protein misfolding and the formation of toxic protein aggregates.In this Review, we summarize the existing literature on a set of aggregation diseases and propose that each of them can be characterized or 'barcoded' by a different set of HSPs that can rescue specific types of aggregation.Interestingly, several of these HSPs also cause diseases when mutated--so-called chaperonopathies--which are also discussed in this Review.

View Article: PubMed Central - PubMed

Affiliation: University Medical Center Groningen, University of Groningen, Department of Cell Biology, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.

ABSTRACT
There are numerous human diseases that are associated with protein misfolding and the formation of toxic protein aggregates. Activating the heat shock response (HSR)--and thus generally restoring the disturbed protein homeostasis associated with such diseases--has often been suggested as a therapeutic strategy. However, most data on activating the HSR or its downstream targets in mouse models of diseases associated with aggregate formation have been rather disappointing. The human chaperonome consists of many more heat shock proteins (HSPs) that are not regulated by the HSR, however, and researchers are now focusing on these as potential therapeutic targets. In this Review, we summarize the existing literature on a set of aggregation diseases and propose that each of them can be characterized or 'barcoded' by a different set of HSPs that can rescue specific types of aggregation. Some of these 'non-canonical' HSPs have demonstrated effectiveness in vivo, in mouse models of protein-aggregation disease. Interestingly, several of these HSPs also cause diseases when mutated--so-called chaperonopathies--which are also discussed in this Review.

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Related in: MedlinePlus

Overview of chaperonopathies caused by mutations in HSPs. Mutations that lead to either recessive (white boxes) or dominant (black boxes) chaperonopathies have been described for six ‘families’ of HSP. Each chaperonopathy is categorized as a neuropathy, myopathy or retina-related disease (cataracts). The mutations in HSPs involved in both recessive and dominant diseases have been shaded gray. h-SP, hereditary-spastic paraplegia; dHMN, distal hereditary motor neuropathy; MN, motor neuropathy; CMT2, Charcot-Marie-Tooth disease 2; DCM, dilated cardiomyopathy; MFM, myofibrillar myopathy; LD, leukodystrophy; MD, muscular dystrophy; CC, congenital cataract; DT, dystrophy.
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f3-0070421: Overview of chaperonopathies caused by mutations in HSPs. Mutations that lead to either recessive (white boxes) or dominant (black boxes) chaperonopathies have been described for six ‘families’ of HSP. Each chaperonopathy is categorized as a neuropathy, myopathy or retina-related disease (cataracts). The mutations in HSPs involved in both recessive and dominant diseases have been shaded gray. h-SP, hereditary-spastic paraplegia; dHMN, distal hereditary motor neuropathy; MN, motor neuropathy; CMT2, Charcot-Marie-Tooth disease 2; DCM, dilated cardiomyopathy; MFM, myofibrillar myopathy; LD, leukodystrophy; MD, muscular dystrophy; CC, congenital cataract; DT, dystrophy.

Mentions: Clinically, genetic chaperonopathies can be categorized into neuropathies [hereditary spastic paraplegia, motor neuropathy, distal hereditary motor neuropathy (dHMN)], myopathies (dilated cardiomyopathy, leukodystrophy, desmin-related myopathy, mitochondrial myopathy, muscular dystrophy) or retina- and eye-lens-related diseases (congenital cataracts) (Macario et al., 2005). Although some chaperonopathies are recessive (and thus probably related to loss of function of the chaperone), most were found to be dominant, as is especially the case for the HSPBs (Table 1). We have labeled or ‘barcoded’ these HSP-associated chaperonopathies depending on the type of disease and mode of inheritance (Fig. 3).


Barcoding heat shock proteins to human diseases: looking beyond the heat shock response.

Kakkar V, Meister-Broekema M, Minoia M, Carra S, Kampinga HH - Dis Model Mech (2014)

Overview of chaperonopathies caused by mutations in HSPs. Mutations that lead to either recessive (white boxes) or dominant (black boxes) chaperonopathies have been described for six ‘families’ of HSP. Each chaperonopathy is categorized as a neuropathy, myopathy or retina-related disease (cataracts). The mutations in HSPs involved in both recessive and dominant diseases have been shaded gray. h-SP, hereditary-spastic paraplegia; dHMN, distal hereditary motor neuropathy; MN, motor neuropathy; CMT2, Charcot-Marie-Tooth disease 2; DCM, dilated cardiomyopathy; MFM, myofibrillar myopathy; LD, leukodystrophy; MD, muscular dystrophy; CC, congenital cataract; DT, dystrophy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3974453&req=5

f3-0070421: Overview of chaperonopathies caused by mutations in HSPs. Mutations that lead to either recessive (white boxes) or dominant (black boxes) chaperonopathies have been described for six ‘families’ of HSP. Each chaperonopathy is categorized as a neuropathy, myopathy or retina-related disease (cataracts). The mutations in HSPs involved in both recessive and dominant diseases have been shaded gray. h-SP, hereditary-spastic paraplegia; dHMN, distal hereditary motor neuropathy; MN, motor neuropathy; CMT2, Charcot-Marie-Tooth disease 2; DCM, dilated cardiomyopathy; MFM, myofibrillar myopathy; LD, leukodystrophy; MD, muscular dystrophy; CC, congenital cataract; DT, dystrophy.
Mentions: Clinically, genetic chaperonopathies can be categorized into neuropathies [hereditary spastic paraplegia, motor neuropathy, distal hereditary motor neuropathy (dHMN)], myopathies (dilated cardiomyopathy, leukodystrophy, desmin-related myopathy, mitochondrial myopathy, muscular dystrophy) or retina- and eye-lens-related diseases (congenital cataracts) (Macario et al., 2005). Although some chaperonopathies are recessive (and thus probably related to loss of function of the chaperone), most were found to be dominant, as is especially the case for the HSPBs (Table 1). We have labeled or ‘barcoded’ these HSP-associated chaperonopathies depending on the type of disease and mode of inheritance (Fig. 3).

Bottom Line: There are numerous human diseases that are associated with protein misfolding and the formation of toxic protein aggregates.In this Review, we summarize the existing literature on a set of aggregation diseases and propose that each of them can be characterized or 'barcoded' by a different set of HSPs that can rescue specific types of aggregation.Interestingly, several of these HSPs also cause diseases when mutated--so-called chaperonopathies--which are also discussed in this Review.

View Article: PubMed Central - PubMed

Affiliation: University Medical Center Groningen, University of Groningen, Department of Cell Biology, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.

ABSTRACT
There are numerous human diseases that are associated with protein misfolding and the formation of toxic protein aggregates. Activating the heat shock response (HSR)--and thus generally restoring the disturbed protein homeostasis associated with such diseases--has often been suggested as a therapeutic strategy. However, most data on activating the HSR or its downstream targets in mouse models of diseases associated with aggregate formation have been rather disappointing. The human chaperonome consists of many more heat shock proteins (HSPs) that are not regulated by the HSR, however, and researchers are now focusing on these as potential therapeutic targets. In this Review, we summarize the existing literature on a set of aggregation diseases and propose that each of them can be characterized or 'barcoded' by a different set of HSPs that can rescue specific types of aggregation. Some of these 'non-canonical' HSPs have demonstrated effectiveness in vivo, in mouse models of protein-aggregation disease. Interestingly, several of these HSPs also cause diseases when mutated--so-called chaperonopathies--which are also discussed in this Review.

Show MeSH
Related in: MedlinePlus