Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors

Crotti, Andrea; Benner, Chris; Kerman, Bilal E.; Gosselin, David; Lagier‐Tourenne, Clotilde; Zuccato, Chiara; Cattaneo, Elena; Gage, Fred H.; Cleveland, Don W.; Glass, Christopher K.

doi:10.1038/nn.3668

Cited by 282 publications

(271 citation statements)

References 54 publications

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“…The abnormally expanded CAG/CAA sequence causes the polyQ overextended mutant protein to be misfolded and dysfunctional, a state believed to result in the diseases' pathology. In addition, these abnormal polyQ proteins are insoluble, and they accumulate and cause cell degeneration [2,3].…”

Section: Introductionmentioning

confidence: 99%

Trehalose Attenuates the Gait Ataxia and Gliosis of Spinocerebellar Ataxia Type 17 Mice

et al. 2015

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Spinocerebellar ataxia type 17 (SCA17) is caused by CAG/CAA repeat expansion on the gene encoding a general transcription factor, TATA-box-binding protein (TBP). The CAG repeat expansion leads to the reduced solubility of polyglutamine TBP and induces aggregate formation. The TBP aggregation, mostly present in the cell nuclei, is distinct from that in most other neurodegenerative diseases, in which the aggregation is formed in cytosol or extracellular compartments. Trehalose is a disaccharide issued by the Food and Drug Administration with a Generally Recognized As Safe status. Lines of evidence suggest trehalose could prevent protein aggregate formation in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. In this study, we evaluated the therapeutic potential of trehalose on SCA17 using cerebellar primary and organotypic culture systems and a mouse model. Our results showed that TBP nuclear aggregation was significantly decreased in both the primary and slice cultures. Trehalose (4 %) was further supplied in the drinking water of SCA17 transgenic mice. We found both the gait behavior in the footprint analysis and motor coordination in the rotarod task were significantly improved in the trehalose-treated SCA17 mice. The cerebellar weight was increased and the astrocyte gliosis was reduced in SCA17 mice after trehalose treatment. These data suggest that trehalose could be a potential nontoxic treatment for SCA17.

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Section: Introductionmentioning

confidence: 99%

Trehalose Attenuates the Gait Ataxia and Gliosis of Spinocerebellar Ataxia Type 17 Mice

et al. 2015

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“…Huntingtin is expressed in immune cells, resulting in cell-autonomous microglial activation and secretion of proinflammatory cytokines, as a consequence of elevated transcription of myeloid lineage-determining factors PU.1 and C/EBPs (CCAAT/enhancer-binding proteins) (Crotti et al 2014). In the peripheral immune system, mutant huntingtin also impacts inflammatory responses through inhibition of NF-kB signaling (Träger et al 2014).…”

Section: Astrocyte and Microglial Dysfunction In Hdmentioning

confidence: 99%

Huntington’s Disease: Mechanisms of Pathogenesis and Therapeutic Strategies

Jimenez-Sanchez

Licitra

Underwood

et al. 2016

Cold Spring Harb Perspect Med

285

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“…16,[104][105][106] The presence of mHtt in astrocytes and other glial cells is associated with age-dependent neurological symptoms, contributes to neuronal excitotoxicity, and can lead to HD pathogenesis. 16,30,[107][108][109][110][111] Specifically, mHtt impairs glycolysis, 112 increases glutamate synthesis, 113 causes a reduction in GABA release, 114 reduces the production and release of trophic factors, 107,115 decreases the expression of potassium channel that leads to neuronal excitotoxicity, 116 and causes a dysfunction in calcium and glutamate signaling. 117 In HD, the abnormal function of microglia can cause an overactivation of the inflammatory response that is like the response seen in other neurodegenerative diseases.…”

Section: 100-103mentioning

confidence: 99%

“…117 In HD, the abnormal function of microglia can cause an overactivation of the inflammatory response that is like the response seen in other neurodegenerative diseases. 109,110 A recent study indicates that mHtt in glia can create a disease phenotype in normal mice, while normal glia can abolish the disease phenotype in transgenic HD mice. This study strongly suggests a causal role for glia in HD.…”

Section: 100-103mentioning

confidence: 99%

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

Blum

Chern

Domenici

et al. 2018

Journal of Caffeine and Adenosine Research

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Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a mutation in the IT15 gene that encodes for the huntingtin protein. Mutated hungtingtin, although widely expressed in the brain, predominantly affects striato-pallidal neurons, particularly enriched with adenosine A 2A receptors (A 2A R), suggesting a possible involvement of adenosine and A 2A R is the pathogenesis of HD. In fact, polymorphic variation in the ADORA2A gene influences the age at onset in HD, and A 2A R dynamics is altered by mutated huntingtin. Basal levels of adenosine and adenosine receptors are involved in many processes critical for neuronal function and homeostasis, including modulation of synaptic activity and excitotoxicity, the control of neurotrophin levels and functions, and the regulation of protein degradation mechanisms. In the present review, we critically analyze the current literature involving the effect of altered adenosine tone and adenosine receptors in HD and discuss why therapeutics that modulate the adenosine system may represent a novel approach for the treatment of HD.Keywords: Huntington's disease, adenosine, adenosine receptors, equilibrative nucleoside transporter, animal models Pathogenic Mechanisms of Huntington's DiseaseOverview H untington's disease (HD) is an inherited neurodegenerative disorder that is caused by a single, autosomal dominant gene mutation. HD generally affects young adults and is characterized by involuntary, abnormal movements and postures (chorea, dyskinesia, dystonia), psychiatric disturbances, and cognitive alterations.1,2 It is estimated that 1 in 10,000 people have HD and this disorder is fatal within 15-20 years after the onset of symptoms. Multiple brain regions, including several cortical and subcortical regions (cerebral cortex, layers III, V, and VI; pallidum, sub-thalamic nucleus, cerebellum), show signs of neurodegeneration, but the most pronounced neuronal loss is present in the caudate nucleus and the putamen of the striatum.3 Within the striatum, the striato-pallidal, medium spiny neurons (MSN) that express enkephalin, dopamine D 2 receptors (D 2 R) and adenosine A 2A receptors (A 2A R), 4,5 appear to be the most vulnerable.6,7

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Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors

Cited by 282 publications

References 54 publications

Trehalose Attenuates the Gait Ataxia and Gliosis of Spinocerebellar Ataxia Type 17 Mice

Trehalose Attenuates the Gait Ataxia and Gliosis of Spinocerebellar Ataxia Type 17 Mice

Huntington’s Disease: Mechanisms of Pathogenesis and Therapeutic Strategies

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

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