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The role of the immune system in triplet repeat expansion diseases.

Olejniczak M, Urbanek MO, Krzyzosiak WJ - Mediators Inflamm. (2015)

Bottom Line: Indeed, a number of immune response markers have been observed in the blood and CNS of patients and mouse models, and the activation of these markers was even observed in the premanifest stage of the disease.Although inflammation is not an initiating factor of TREDs, growing evidence indicates that inflammatory responses involving astrocytes, microglia, and the peripheral immune system may contribute to disease progression.We also present various therapeutic approaches targeting the dysregulated inflammation pathways in these diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland.

ABSTRACT
Trinucleotide repeat expansion disorders (TREDs) are a group of dominantly inherited neurological diseases caused by the expansion of unstable repeats in specific regions of the associated genes. Expansion of CAG repeat tracts in translated regions of the respective genes results in polyglutamine- (polyQ-) rich proteins that form intracellular aggregates that affect numerous cellular activities. Recent evidence suggests the involvement of an RNA toxicity component in polyQ expansion disorders, thus increasing the complexity of the pathogenic processes. Neurodegeneration, accompanied by reactive gliosis and astrocytosis is the common feature of most TREDs, which may suggest involvement of inflammation in pathogenesis. Indeed, a number of immune response markers have been observed in the blood and CNS of patients and mouse models, and the activation of these markers was even observed in the premanifest stage of the disease. Although inflammation is not an initiating factor of TREDs, growing evidence indicates that inflammatory responses involving astrocytes, microglia, and the peripheral immune system may contribute to disease progression. Herein, we review the involvement of the immune system in the pathogenesis of triplet repeat expansion diseases, with particular emphasis on polyglutamine disorders. We also present various therapeutic approaches targeting the dysregulated inflammation pathways in these diseases.

No MeSH data available.


Related in: MedlinePlus

Inflammation in Huntington's disease. The mutant HTT transcript and protein are expressed in many cell types, including neurons, astrocytes, and blood cells of HD patients. The pathogenic effect may be triggered by expanded CAG repeat hairpins, cytoplasmic protein aggregates, N-terminal fragments of huntingtin, or toxic frameshifting products, and so forth. It is currently not clear what pathways are primarily involved in inducing the inflammatory response observed in the CNS and peripheral immune system. This effect is observed in the brain and peripheral tissues, indicating crosstalk in the signaling between distant tissues. The observed immune effects include elevated cytokine levels, caspase pathways activation, induction of apoptosis, dysregulation of gene expression, or decreased immune cell migration.
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Related In: Results  -  Collection


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fig1: Inflammation in Huntington's disease. The mutant HTT transcript and protein are expressed in many cell types, including neurons, astrocytes, and blood cells of HD patients. The pathogenic effect may be triggered by expanded CAG repeat hairpins, cytoplasmic protein aggregates, N-terminal fragments of huntingtin, or toxic frameshifting products, and so forth. It is currently not clear what pathways are primarily involved in inducing the inflammatory response observed in the CNS and peripheral immune system. This effect is observed in the brain and peripheral tissues, indicating crosstalk in the signaling between distant tissues. The observed immune effects include elevated cytokine levels, caspase pathways activation, induction of apoptosis, dysregulation of gene expression, or decreased immune cell migration.

Mentions: Taken together, the results of numerous studies show that immune system activation contributes to the neurodegeneration observed in HD and that the interplay between neurons, astrocytes, and microglia is responsible for these effects at the CNS level (Figure 1).


The role of the immune system in triplet repeat expansion diseases.

Olejniczak M, Urbanek MO, Krzyzosiak WJ - Mediators Inflamm. (2015)

Inflammation in Huntington's disease. The mutant HTT transcript and protein are expressed in many cell types, including neurons, astrocytes, and blood cells of HD patients. The pathogenic effect may be triggered by expanded CAG repeat hairpins, cytoplasmic protein aggregates, N-terminal fragments of huntingtin, or toxic frameshifting products, and so forth. It is currently not clear what pathways are primarily involved in inducing the inflammatory response observed in the CNS and peripheral immune system. This effect is observed in the brain and peripheral tissues, indicating crosstalk in the signaling between distant tissues. The observed immune effects include elevated cytokine levels, caspase pathways activation, induction of apoptosis, dysregulation of gene expression, or decreased immune cell migration.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4385693&req=5

fig1: Inflammation in Huntington's disease. The mutant HTT transcript and protein are expressed in many cell types, including neurons, astrocytes, and blood cells of HD patients. The pathogenic effect may be triggered by expanded CAG repeat hairpins, cytoplasmic protein aggregates, N-terminal fragments of huntingtin, or toxic frameshifting products, and so forth. It is currently not clear what pathways are primarily involved in inducing the inflammatory response observed in the CNS and peripheral immune system. This effect is observed in the brain and peripheral tissues, indicating crosstalk in the signaling between distant tissues. The observed immune effects include elevated cytokine levels, caspase pathways activation, induction of apoptosis, dysregulation of gene expression, or decreased immune cell migration.
Mentions: Taken together, the results of numerous studies show that immune system activation contributes to the neurodegeneration observed in HD and that the interplay between neurons, astrocytes, and microglia is responsible for these effects at the CNS level (Figure 1).

Bottom Line: Indeed, a number of immune response markers have been observed in the blood and CNS of patients and mouse models, and the activation of these markers was even observed in the premanifest stage of the disease.Although inflammation is not an initiating factor of TREDs, growing evidence indicates that inflammatory responses involving astrocytes, microglia, and the peripheral immune system may contribute to disease progression.We also present various therapeutic approaches targeting the dysregulated inflammation pathways in these diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland.

ABSTRACT
Trinucleotide repeat expansion disorders (TREDs) are a group of dominantly inherited neurological diseases caused by the expansion of unstable repeats in specific regions of the associated genes. Expansion of CAG repeat tracts in translated regions of the respective genes results in polyglutamine- (polyQ-) rich proteins that form intracellular aggregates that affect numerous cellular activities. Recent evidence suggests the involvement of an RNA toxicity component in polyQ expansion disorders, thus increasing the complexity of the pathogenic processes. Neurodegeneration, accompanied by reactive gliosis and astrocytosis is the common feature of most TREDs, which may suggest involvement of inflammation in pathogenesis. Indeed, a number of immune response markers have been observed in the blood and CNS of patients and mouse models, and the activation of these markers was even observed in the premanifest stage of the disease. Although inflammation is not an initiating factor of TREDs, growing evidence indicates that inflammatory responses involving astrocytes, microglia, and the peripheral immune system may contribute to disease progression. Herein, we review the involvement of the immune system in the pathogenesis of triplet repeat expansion diseases, with particular emphasis on polyglutamine disorders. We also present various therapeutic approaches targeting the dysregulated inflammation pathways in these diseases.

No MeSH data available.


Related in: MedlinePlus