Heat shock proteins in neurodegenerative diseases: Pathogenic roles and therapeutic implications

Figures & data

Figure 1. Diagram showing the roles of chaperones in folding of proteins and degradation of misfolded proteins. It has been suggested that a pathogenic process leads to formation of misfolded conformations of the target protein in neurodegenerative diseases. Correct protein folding is an essential biological process, and to achieve this, many proteins interact with molecular chaperones in the cellular environment. The Hsp70 class of molecular chaperones recognises the unfolded substrate early in the folding process, and maintains the polypeptide in the soluble conformation. To facilitate protein folding, Hsp70 interacts with its co-chaperones that regulate its chaperone activity. A major class of Hsp70 co-chaperone proteins is the Hsp40 family. Both Hsp70 and the Hsp40 family of chaperones have been shown to interact with the E3 ubiquitin ligases, particularly the quality-control E3 ligases, and are implicated in the biology of neurodegenerative disorders involving protein misfolding. Quality-control E3 ligases like CHIP could specifically target misfolded mutant disease proteins for proteasomal degradation and thereby could potentially slow disease progression.

Table I.  Changes in chaperone expression in neurodegenerative diseases.

Disease	Chaperones	References
SBMA	Hsp70↓	Katsuno et al. [18]
HD	Hsp70↓, Hsp40↓	Hay et al. [15]
	α B-crystalin↓	Zabel et al. [16]
SCA7	Hsp70↓, Hsp27↓	Tsai et al. [20]
ALS	Hsp25↓	Maatkamp et al. [21]
PD	Hsc70↓	Grunblatt et al. [19]

SBMA, spinal and bulbar muscular atrophy; HD, Huntington's disease; SCA7, spinocerebellar ataxia type 7; ALS, amyotrophic lateral sclerosis; PD, Parkinson's disease.

Table II.  Compounds that induce chaperone expression.

Compound	Molecular weight	Therapeutic effects	Change in chaperones	Clinical use
Cell			Animal
GGA	330.55	SBMA [18]	SBMA [18]	Hsp105↑↑	Anti-ulcer drug
				Hsp90↑
				Hsp70↑↑↑
17-AAG	585.69	SBMA [41], [61]	SBMA [41], [61]	Hsp90→	Anti-cancer drug
17-DMAG	652	HD [42]	PD [50]	Hsp70↑↑↑
		ALS [48]		Hsp40↑↑↑
Celastrol	450.61	HD [33]	HD [36]	Hsp70↑↑
			PD [36]
			ALS [49]
Arimoclomol	313.78		ALS [34]	Hsp90↑↑	ALS
				Hsp70↑↑↑
				Hsp27↑↑

GGA, Geranylgeranylacetone; 17-AAG, 17-allylamino-17-demethoxygeldanamycin; 17-DMAG, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; SBMA, spinal and bulbar muscular atrophy; HD, Huntington's disease; PD, Parkinson's disease; ALS: amyotrophic lateral sclerosis.

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