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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

The intra-cellular sites of toxic effects of proteins in polyQ disorders. PolyQ aggregates induce cytotoxic effects through a range of mechanisms. To form insoluble inclusions, compiling of polyQ-expanded protein provoke quality-control mechanisms including ubiquitin–proteasome system, chaperones and autophagy. By interacting with transcriptional factors, the toxic polyQ proteins could regulate transcriptional processes. Other cellular sites of toxic effects induced by polyQ mutant proteins include Ca2+ channel, mitochondria, and cytoskeleton with diverse abnormalities respectively.
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Fig1: The intra-cellular sites of toxic effects of proteins in polyQ disorders. PolyQ aggregates induce cytotoxic effects through a range of mechanisms. To form insoluble inclusions, compiling of polyQ-expanded protein provoke quality-control mechanisms including ubiquitin–proteasome system, chaperones and autophagy. By interacting with transcriptional factors, the toxic polyQ proteins could regulate transcriptional processes. Other cellular sites of toxic effects induced by polyQ mutant proteins include Ca2+ channel, mitochondria, and cytoskeleton with diverse abnormalities respectively.

Mentions: Insoluble aggregates present toxic effects for neurons and result in cell death and organism pathology [11]. PolyQ diseases seem to be originated by proteolytic cleavage of mutant protein containing polyQ-expanded tract to form toxic fragments [9, 10], which aberrantly fold into amyloid-like aggregates (oligomers), then assemble into nuclear and cytoplasmic deposits which are the cellular hallmarks of polyQ diseases. The neuronal protein aggregates mainly present in nucleus (SCA1, SCA2, SCA3/MJD, SCA7, SCA17 and DRPLA), cytoplasm (SCA6) or both cytoplasm and nucleus (HD and SBMA) (Figure 1) [76, 77].Figure 1


Alleviating neurodegeneration in Drosophila models of PolyQ diseases.

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

The intra-cellular sites of toxic effects of proteins in polyQ disorders. PolyQ aggregates induce cytotoxic effects through a range of mechanisms. To form insoluble inclusions, compiling of polyQ-expanded protein provoke quality-control mechanisms including ubiquitin–proteasome system, chaperones and autophagy. By interacting with transcriptional factors, the toxic polyQ proteins could regulate transcriptional processes. Other cellular sites of toxic effects induced by polyQ mutant proteins include Ca2+ channel, mitochondria, and cytoskeleton with diverse abnormalities respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: The intra-cellular sites of toxic effects of proteins in polyQ disorders. PolyQ aggregates induce cytotoxic effects through a range of mechanisms. To form insoluble inclusions, compiling of polyQ-expanded protein provoke quality-control mechanisms including ubiquitin–proteasome system, chaperones and autophagy. By interacting with transcriptional factors, the toxic polyQ proteins could regulate transcriptional processes. Other cellular sites of toxic effects induced by polyQ mutant proteins include Ca2+ channel, mitochondria, and cytoskeleton with diverse abnormalities respectively.
Mentions: Insoluble aggregates present toxic effects for neurons and result in cell death and organism pathology [11]. PolyQ diseases seem to be originated by proteolytic cleavage of mutant protein containing polyQ-expanded tract to form toxic fragments [9, 10], which aberrantly fold into amyloid-like aggregates (oligomers), then assemble into nuclear and cytoplasmic deposits which are the cellular hallmarks of polyQ diseases. The neuronal protein aggregates mainly present in nucleus (SCA1, SCA2, SCA3/MJD, SCA7, SCA17 and DRPLA), cytoplasm (SCA6) or both cytoplasm and nucleus (HD and SBMA) (Figure 1) [76, 77].Figure 1

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