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The Role of Microglia and Astrocytes in Huntington's Disease.

ABSTRACT: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease. HD patients present with movement disorders, behavioral and psychiatric symptoms and cognitive decline. This review summarizes the contribution of microglia and astrocytes to HD pathophysiology. Neuroinflammation in the HD brain is characterized by a reactive morphology in these glial cells. Microglia and astrocytes are critical in regulating neuronal activity and maintaining an optimal milieu for neuronal function. Previous studies provide evidence that activated microglia and reactive astrocytes contribute to HD pathology through transcriptional activation of pro-inflammatory genes to perpetuate a chronic inflammatory state. Reactive astrocytes also display functional changes in glutamate and ion homeostasis and energy metabolism. Astrocytic and microglial changes may further contribute to the neuronal death observed with the progression of HD. Importantly, the degree to which these neuroinflammatory changes are detrimental to neurons and contribute to the progression of HD pathology is not well understood. Furthermore, recent observations provide compelling evidence that activated microglia and astrocytes exert a variety of beneficial functions that are essential for limiting tissue damage and preserving neuronal function in the HD brain. Therefore, a better understanding of the neuroinflammatory environment in the brain in HD may lead to the development of targeted and innovative therapeutic opportunities.

SUBMITTER: Palpagama TH

PROVIDER: S-EPMC6824292 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Role of Microglia and Astrocytes in Huntington's Disease.

Palpagama Thulani H TH Waldvogel Henry J HJ Faull Richard L M RLM Kwakowsky Andrea A

Frontiers in molecular neuroscience 20191025

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease. HD patients present with movement disorders, behavioral and psychiatric symptoms and cognitive decline. This review summarizes the contribution of microglia and astrocytes to HD pathophysiology. Neuroinflammation in the HD brain is characterized by a reactive morphology in these glial cells. Microglia and astrocytes are critical in regulating neuronal activity and maintaining an optimal milieu for neuronal function. Pr ...[more]

PMID: 31708741

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Project description:Huntington's disease (HD) is a devastating monogenic, dominant, hereditary, neurodegenerative disease. HD is caused by the expansion of CAG repeats in exon 1 of the huntingtin (HTT) gene, IT15, resulting in an expanded polyglutamine (polyQ) residue in the N-terminus of the HTT protein. HD is characterized by the accumulation of mutant HTT (mHTT) in neural and somatic cells. Progressive brain atrophy occurs initially in the striatum and extends to different brain regions with progressive decline in cognitive, behavioral and motor functions. Astrocytes are the most abundant cell type in the brain and play an essential role in neural development and maintaining homeostasis in the central nervous system (CNS). There is increasing evidence supporting the involvement of astrocytes in the development of neurodegenerative diseases such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). We have generated neural progenitor cells (NPCs) from induced pluripotent stem cells (iPSCs) of transgenic HD monkeys as a model for studying HD pathogenesis. We have reported that NPCs can be differentiated in vitro into mature neural cells, such as neurons and glial cells, and are an excellent tool to study the pathogenesis of HD. To better understand the role of astrocytes in HD pathogenesis and discover new therapies to treat HD, we have developed an astrocyte differentiation protocol and evaluated the efficacy of RNAi to ameliorate HD phenotypes in astrocytes. The resultant astrocytes expressed canonical astrocyte-specific markers examined by immunostaining and real-time PCR. Flow cytometry (FACS) analysis showed that the majority of the differentiated NPCs (95.7%) were positive for an astrocyte specific marker, glial fibrillary acidic protein (GFAP). Functionalities of astrocytes were evaluated by glutamate uptake assay and electrophysiology. Expression of mHTT in differentiated astrocytes induced cytosolic mHTT aggregates and nuclear inclusions, suppressed the expression of SOD2 and PGC1, reduced ability to uptake glutamate, decreased 4-aminopyridine (4-AP) response, and shifted I/V plot measured by electrophysiology, which are consistent with previous reports on HD astrocytes and patient brain samples. However, expression of small-hairpin RNA against HTT (shHD) ameliorated and reversed aforementioned HD phenotypes in astrocytes. This represents a demonstration of a novel non-human primate (NHP) astrocyte model for studying HD pathogenesis and a platform for discovering novel HD treatments.

Project description:BACKGROUND:Newcastle disease (ND), which is caused by infections of poultry species with virulent strains of Avian orthoavulavirus-1, also known as avian paramyxovirus 1 (APMV-1), and formerly known as Newcastle disease virus (NDV), may cause neurological signs and encephalitis. Neurological signs are often the only clinical signs observed in birds infected with neurotropic strains of NDV. Experimental infections have shown that the replication of virulent NDV (vNDV) strains is in the brain parenchyma and is possibly confined to neurons and ependymal cells. However, little information is available on the ability of vNDV strains to infect subset of glial cells (astrocytes, oligodendrocytes, and microglia). The objective of this study was to evaluate the ability of NDV strains of different levels of virulence to infect a subset of glial cells both in vitro and in vivo. Thus, neurons, astrocytes and oligodendrocytes from the brains of day-old White Leghorn chickens were harvested, cultured, and infected with both non-virulent (LaSota) and virulent, neurotropic (TxGB) NDV strains. To confirm these findings in vivo, the tropism of three vNDV strains with varying pathotypes (SA60 [viscerotropic], TxGB [neurotropic], and Tx450 [mesogenic]) was assessed in archived formalin-fixed material from day-old chicks inoculated intracerebrally. RESULTS:Double immunofluorescence for NDV nucleoprotein and cellular markers showed that both strains infected at least 20% of each of the cell types (neurons, astrocytes, and oligodendrocytes). At 24 h post-inoculation, TxGB replicated significantly more than LaSota. Double immunofluorescence (DIFA) with markers for neurons, astrocytes, microglia, and NDV nucleoprotein detected the three strains in all three cell types at similar levels. CONCLUSION:These data indicate that similar to other paramyxoviruses, neurons and glial cells (astrocytes, oligodendrocytes, and microglia) are susceptible to vNDV infection, and suggest that factors other than cellular tropism are likely the major determinant of the neurotropic phenotype.

Project description:BackgroundHuntington's Disease (HD) is a devastating neurodegenerative disorder that clinically manifests as motor dysfunction, cognitive impairment and psychiatric symptoms. There is currently no cure for this progressive and fatal disorder. The causative mutation of this hereditary disease is a trinucleotide repeat expansion (CAG) in the Huntingtin gene that results in an expanded polyglutamine tract. Multiple mechanisms have been proposed to explain the preferential striatal and cortical degeneration that occurs with HD, including non-cell-autonomous contribution from astrocytes. Although numerous cell culture and animal models exist, there is a great need for experimental systems that can more accurately replicate the human disease. Human induced pluripotent stem cells (iPSCs) are a remarkable new tool to study neurological disorders because this cell type can be derived from patients as a renewable, genetically tractable source for unlimited cells that are difficult to acquire, such as neurons and astrocytes. The development of experimental systems based on iPSC technology could aid in the identification of molecular lesions and therapeutic treatments.ResultsWe derived iPSCs from a father with adult onset HD and 50 CAG repeats (F-HD-iPSC) and his daughter with juvenile HD and 109 CAG repeats (D-HD-iPSC). These disease-specific iPSC lines were characterized by standard assays to assess the quality of iPSC lines and to demonstrate their pluripotency. HD-iPSCs were capable of producing phenotypically normal, functional neurons in vitro and were able to survive and differentiate into neurons in the adult mouse brain in vivo after transplantation. Surprisingly, when HD-iPSCs were directed to differentiate into an astrocytic lineage, we observed the presence of cytoplasmic, electron clear vacuoles in astrocytes from both F-HD-iPSCs and D-HD-iPSCs, which were significantly more pronounced in D-HD-astrocytes. Remarkably, the vacuolation in diseased astrocytes was observed under basal culture conditions without additional stressors and increased over time. Importantly, similar vacuolation phenotype has also been observed in peripheral blood lymphocytes from individuals with HD. Together, these data suggest that vacuolation may be a phenotype associated with HD.ConclusionsWe have generated a unique in vitro system to study HD pathogenesis using patient-specific iPSCs. The astrocytes derived from patient-specific iPSCs exhibit a vacuolation phenotype, a phenomenon previously documented in primary lymphocytes from HD patients. Our studies pave the way for future mechanistic investigations using human iPSCs to model HD and for high-throughput therapeutic screens.

Dataset Information

The Role of Microglia and Astrocytes in Huntington's Disease.

Publications

The Role of Microglia and Astrocytes in Huntington's Disease.

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