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Alleviating neurodegeneration in Drosophila models of PolyQ diseases.

Long Z, Tang B, Jiang H - Cerebellum Ataxias (2014)

Bottom Line: Polyglutamine (polyQ) diseases are a group of neurodegenerative conditions, induced from CAG trinucleotide repeat expansion within causative gene respectively.Generation of toxic proteins, containing polyQ-expanded tract, is the key process to cause neurodegeneration.Till now, although polyQ diseases remain uncurable, numerous therapeutic strategies with great potential have been examined and have been proven to be effective against polyQ diseases, including diverse small biological molecules and many pharmacological compounds mainly through prevention on formation of aggregates and inclusions, acceleration on degradation of toxic proteins and regulation of cellular function.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Xiangya Hospital, Central South University, 87 Xiangya road, Changsha, 410008 Hunan China.

ABSTRACT
Polyglutamine (polyQ) diseases are a group of neurodegenerative conditions, induced from CAG trinucleotide repeat expansion within causative gene respectively. Generation of toxic proteins, containing polyQ-expanded tract, is the key process to cause neurodegeneration. Till now, although polyQ diseases remain uncurable, numerous therapeutic strategies with great potential have been examined and have been proven to be effective against polyQ diseases, including diverse small biological molecules and many pharmacological compounds mainly through prevention on formation of aggregates and inclusions, acceleration on degradation of toxic proteins and regulation of cellular function. We review promising therapeutic strategies by using Drosophila models of polyQ diseases including HD, SCA1, SCA3 and SBMA.

No MeSH data available.


Related in: MedlinePlus

SCA3/MJDDrosophilathat expresses polyQ-expanded tracts in fly compound eyes. Overexpression of Hsp22, VPA and LiCl rescues polyQ-induced eye depigmentation in Drosophila model of SCA3/MJD. (A) Hsp22, (B) VPA, (C) LiCl. Paired images of adult fly eyes are showing, dissecting microscope (A, ×65; B, ×115; C, ×80) and electron microscope (×1000).
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Fig2: SCA3/MJDDrosophilathat expresses polyQ-expanded tracts in fly compound eyes. Overexpression of Hsp22, VPA and LiCl rescues polyQ-induced eye depigmentation in Drosophila model of SCA3/MJD. (A) Hsp22, (B) VPA, (C) LiCl. Paired images of adult fly eyes are showing, dissecting microscope (A, ×65; B, ×115; C, ×80) and electron microscope (×1000).

Mentions: Accumulation of aggregates to form inclusions recruits cellular normal proteins, such as molecular chaperones, which suggests that polyQ-expanded domain changes protein structure and activates chaperones against protein misfolding [82]. The finding that expanded polyQ tract is capable of transiting into diverse conformations is also affirmed by evidence that, in fly (SCA3/MJD, HD) and mouse (SCA1) models, overexpression of molecular chaperones represses toxicity [83, 84]. Thus, several biological molecules may thought to be potential therapeutics targeting prevention on formation of pathogenic aggregates and toxic structure of polyQ proteins, such as polyglutamine binding peptide 1 (QBP1), a peptide P42, chaperones heat shock proteins including heat shock protein 70 (Hsp70), Hsp40, Hsp110 and Hsp22. Application of QBP1 which is capable of selectively binding to the polyQ-expanded stretch suppresses compound eye degeneration, polyQ aggregates formation and rescues premature death in SCA3/MJD Drosophila model [56], suggesting that QBP1 is a potential therapeutic molecule on polyQ disorders. P42, a 23 amino acid-long peptide which is a part of the endogenous Htt protein, plays a protective role in preventing polyQ-hHtt aggregation, improving the impaired axonal transport by restoring the total number and motion of vesicles, ameliorating behavioral dysfunctions and against polyQ-hHtt induced toxicity in HD Drosophila model. However, no protective effects were found in other polyQ diseases [57]. Although the toxic conformation of polyQ proteins remains elusive, therapeutic strategy targeting on toxic structure of expanded polyglutamine proteins may be a promising approach against untreatable polyQ disease. In Drosophila melanogaster model of SCA3/MJD, co-expressing the human gene HSPA1L which encodes Hsp70, Warrick et al. discovered that Hsp70 completely rescued external eye pigmentation, partially restored retinal structure of brain, and partially restored adult viability, suggesting that molecular chaperone Hsp70 suppresses polyglutamine-induced neurodegeneration and toxicity as well as indicating that HSP70 would be a promising candidate with great potential as a treatment method [58]. Additionally, in a Drosophila model of SBMA, Adrienne et al. demonstrated that Hsp70 with its co-chaperone Hip which enhances Hsp70 binding to its substrates accelerated polyQ AR clearance, and identified that Hsp70 with YM-1, a synthetic co-chaperone that acts similarly to Hip, also enhanced polyQ AR degradation and suppressed toxicity of poyQ AR in Drosophila[59]. Similarly, Kazemi et al. by screening the fly genome for genes modulating the toxicity of polyglutamine, predicted dHDJ1, homologous to human Hsp40/HDJ1, and dTPR2, homologous to the human tetratricopeptide repeat protein 2 (TPR2) suppressed the toxicity of polyQ aggregates and verified in Drosophila models of polyQ diseases [49]. In addition, Y Kuo el at further demonstrated that co-expression of the HSP40 family protein DNAJ-1 and Hsp110 family protein, 70 kDa heat-shock cognate protein cb (HSC70cb), function together to suppress the cytotoxicity of mutated huntingtin in Drosophila HD model. Furthermore, DNAJB1, a human Hsp40, co-expressed with APG-1, a human Hsp110, in cells from HD Drosophila had a dramatic protective effect on polyQ-induced neural degeneration, whereas either component alone had little effect [60]. In our previous studies, using several types of SCA3/MJD Drosophila models, we have provided convincing proof that Hsp22 would be promising therapeutic agents with great potential against SCA3/MJD. Expression of MJDtr-Q78, a polyQ-expanded tract, showed significantly obvious SCA3/MJD phenotype including dramatic neurodegeneration, and completely faded pigmentation in adult flies with black point-like necrosis. Drosophila co-expressed polyQ-expanded protein together with either one or two copies of HSP22 gene intervened by heat shock, leading to differing corresponding mRNA levels mainly depending on the induced number of HSP22 gene copies. Findings suggested that Hsp22 showed positive influence on eye depigmentation (Figure 2), growth restriction, ability for eclosion and median lifespan [61].Figure 2


Alleviating neurodegeneration in Drosophila models of PolyQ diseases.

Long Z, Tang B, Jiang H - Cerebellum Ataxias (2014)

SCA3/MJDDrosophilathat expresses polyQ-expanded tracts in fly compound eyes. Overexpression of Hsp22, VPA and LiCl rescues polyQ-induced eye depigmentation in Drosophila model of SCA3/MJD. (A) Hsp22, (B) VPA, (C) LiCl. Paired images of adult fly eyes are showing, dissecting microscope (A, ×65; B, ×115; C, ×80) and electron microscope (×1000).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4552282&req=5

Fig2: SCA3/MJDDrosophilathat expresses polyQ-expanded tracts in fly compound eyes. Overexpression of Hsp22, VPA and LiCl rescues polyQ-induced eye depigmentation in Drosophila model of SCA3/MJD. (A) Hsp22, (B) VPA, (C) LiCl. Paired images of adult fly eyes are showing, dissecting microscope (A, ×65; B, ×115; C, ×80) and electron microscope (×1000).
Mentions: Accumulation of aggregates to form inclusions recruits cellular normal proteins, such as molecular chaperones, which suggests that polyQ-expanded domain changes protein structure and activates chaperones against protein misfolding [82]. The finding that expanded polyQ tract is capable of transiting into diverse conformations is also affirmed by evidence that, in fly (SCA3/MJD, HD) and mouse (SCA1) models, overexpression of molecular chaperones represses toxicity [83, 84]. Thus, several biological molecules may thought to be potential therapeutics targeting prevention on formation of pathogenic aggregates and toxic structure of polyQ proteins, such as polyglutamine binding peptide 1 (QBP1), a peptide P42, chaperones heat shock proteins including heat shock protein 70 (Hsp70), Hsp40, Hsp110 and Hsp22. Application of QBP1 which is capable of selectively binding to the polyQ-expanded stretch suppresses compound eye degeneration, polyQ aggregates formation and rescues premature death in SCA3/MJD Drosophila model [56], suggesting that QBP1 is a potential therapeutic molecule on polyQ disorders. P42, a 23 amino acid-long peptide which is a part of the endogenous Htt protein, plays a protective role in preventing polyQ-hHtt aggregation, improving the impaired axonal transport by restoring the total number and motion of vesicles, ameliorating behavioral dysfunctions and against polyQ-hHtt induced toxicity in HD Drosophila model. However, no protective effects were found in other polyQ diseases [57]. Although the toxic conformation of polyQ proteins remains elusive, therapeutic strategy targeting on toxic structure of expanded polyglutamine proteins may be a promising approach against untreatable polyQ disease. In Drosophila melanogaster model of SCA3/MJD, co-expressing the human gene HSPA1L which encodes Hsp70, Warrick et al. discovered that Hsp70 completely rescued external eye pigmentation, partially restored retinal structure of brain, and partially restored adult viability, suggesting that molecular chaperone Hsp70 suppresses polyglutamine-induced neurodegeneration and toxicity as well as indicating that HSP70 would be a promising candidate with great potential as a treatment method [58]. Additionally, in a Drosophila model of SBMA, Adrienne et al. demonstrated that Hsp70 with its co-chaperone Hip which enhances Hsp70 binding to its substrates accelerated polyQ AR clearance, and identified that Hsp70 with YM-1, a synthetic co-chaperone that acts similarly to Hip, also enhanced polyQ AR degradation and suppressed toxicity of poyQ AR in Drosophila[59]. Similarly, Kazemi et al. by screening the fly genome for genes modulating the toxicity of polyglutamine, predicted dHDJ1, homologous to human Hsp40/HDJ1, and dTPR2, homologous to the human tetratricopeptide repeat protein 2 (TPR2) suppressed the toxicity of polyQ aggregates and verified in Drosophila models of polyQ diseases [49]. In addition, Y Kuo el at further demonstrated that co-expression of the HSP40 family protein DNAJ-1 and Hsp110 family protein, 70 kDa heat-shock cognate protein cb (HSC70cb), function together to suppress the cytotoxicity of mutated huntingtin in Drosophila HD model. Furthermore, DNAJB1, a human Hsp40, co-expressed with APG-1, a human Hsp110, in cells from HD Drosophila had a dramatic protective effect on polyQ-induced neural degeneration, whereas either component alone had little effect [60]. In our previous studies, using several types of SCA3/MJD Drosophila models, we have provided convincing proof that Hsp22 would be promising therapeutic agents with great potential against SCA3/MJD. Expression of MJDtr-Q78, a polyQ-expanded tract, showed significantly obvious SCA3/MJD phenotype including dramatic neurodegeneration, and completely faded pigmentation in adult flies with black point-like necrosis. Drosophila co-expressed polyQ-expanded protein together with either one or two copies of HSP22 gene intervened by heat shock, leading to differing corresponding mRNA levels mainly depending on the induced number of HSP22 gene copies. Findings suggested that Hsp22 showed positive influence on eye depigmentation (Figure 2), growth restriction, ability for eclosion and median lifespan [61].Figure 2

Bottom Line: Polyglutamine (polyQ) diseases are a group of neurodegenerative conditions, induced from CAG trinucleotide repeat expansion within causative gene respectively.Generation of toxic proteins, containing polyQ-expanded tract, is the key process to cause neurodegeneration.Till now, although polyQ diseases remain uncurable, numerous therapeutic strategies with great potential have been examined and have been proven to be effective against polyQ diseases, including diverse small biological molecules and many pharmacological compounds mainly through prevention on formation of aggregates and inclusions, acceleration on degradation of toxic proteins and regulation of cellular function.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Xiangya Hospital, Central South University, 87 Xiangya road, Changsha, 410008 Hunan China.

ABSTRACT
Polyglutamine (polyQ) diseases are a group of neurodegenerative conditions, induced from CAG trinucleotide repeat expansion within causative gene respectively. Generation of toxic proteins, containing polyQ-expanded tract, is the key process to cause neurodegeneration. Till now, although polyQ diseases remain uncurable, numerous therapeutic strategies with great potential have been examined and have been proven to be effective against polyQ diseases, including diverse small biological molecules and many pharmacological compounds mainly through prevention on formation of aggregates and inclusions, acceleration on degradation of toxic proteins and regulation of cellular function. We review promising therapeutic strategies by using Drosophila models of polyQ diseases including HD, SCA1, SCA3 and SBMA.

No MeSH data available.


Related in: MedlinePlus