Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms

Abstract

Huntington disease (HD) is an inherited neurological disorder caused by a polyglutamine expansion in the protein huntingtin and is characterized by selective neurodegeneration that preferentially occurs in striatal medium spiny neurons. Because the medium spiny neurons are innervated abundantly by glutamatergic axons from cortical neurons, the preferential degeneration in the striatal neurons supports the glutamate excitotoxicity theory for HD pathogenesis. Thus, glutamate uptake by glia may be particularly important for preventing glutamate excitotoxicity in HD. Although mutant huntingtin is expressed ubiquitously in various types of cells, it accumulates and forms aggregates in fewer glial cells than in neuronal cells. It remains largely unknown whether and how mutant huntingtin in glia can contribute to the neurological symptoms of HD. We generated transgenic mice that express N-terminal mutant huntingtin in astrocytes, a major type of glial cell that remove extracellular glutamate in the brain. Although transgenic mutant huntingtin in astrocytes is expressed below the endogenous level, it can cause age-dependent neurological phenotypes in transgenic mice. Mice expressing mutant huntingtin show body weight loss, have motor function deficits, and die earlier than wild-type or control transgenic mice. We also found that mutant huntingtin in astrocytes decreases the expression of glutamate transporter by increasing its binding to Sp1 and reducing the association of Sp1 with the promoter of glutamate transporter. These results imply an important role for glial mutant huntingtin in HD pathology and suggest possibilities for treatment.excitotoxicity ͉ glia ͉ neurodegeneration ͉ polyglutamine ͉ glutamate I n Huntington disease (HD), selective neuronal loss occurs preferentially in medium spiny neurons of the striatum and then extends to other brain regions as the disease progresses (1). Because medium spiny neurons are innervated by glutamatergic axons from cortical neurons (2), they are particularly vulnerable to glutamate excitotoxicity, a possible pathogenic mechanism for the preferential neurodegeneration seen in the striatum of HD patients (3). In support of this theory, excitotoxicity of the NMDA receptor, an ionotropic receptor for glutamate, is now associated with HD in various animal models (4, 5).The majority of cells in the brain are glia that support the survival of neuronal cells. Astrocytes are the major type of glia and express glutamate transporters that uptake extracellular glutamate to prevent glutamate neurotoxicity (6-8). Although mutant huntingtin (htt) is expressed in glial cells in the brains of HD mice and patients (9, 10), whether and how mutant htt in glia contributes to neuropathology in vivo remains unknown. Because glial cells can be therapeutic targets, establishing a transgenic mouse model expressing mutant htt specifically in glia can help develop treatment for HD.Current HD mouse models have limitations for studying glial htt contribution, because transgenic htt in these HD mice is e...

Rapamycin prevents the mutant huntingtin-suppressed GLT-1 expression in cultured astrocytes

“…Consistent with prior research, we have provided direct evidence that mutant Htt-552 in glial cells reduced the expression of GLT-1 but not of GLAST and decreased glutamate uptake in astrocytes, which was mainly caused by decreased expression of GLT-1. Because there are Sp1-binding sites in the promoter of GLT-1 and the transcription of GLT-1 is Sp1-dependent [24,25] , previous reports of mutant Htt binding more Sp1 and reducing Sp1-mediated GLT-1 expression in astrocytes may explain this www.chinaphar.com Chen LL et al Acta Pharmacologica Sinica npg phenomenon [10] .…”

“…The transcription of GLT-1 was Sp1-dependent, and it had been reported that mutant Htt bound more Sp1 and reduced Sp1-mediated GLT-1 expression in astrocytes. This could lead to defective glial glutamate uptake and increased neuronal excitotoxicity [10] . Therefore, we want to know if the expression of GLT-1 would return to a normal level after mutant Htt had been cleared.…”

The endocannabinoid system in normal and pathological brain ageing

“…In the brain of patients suffering from neurodegenerative diseases [138][139][140] and in animal models of these disorders [141][142][143][144], signs of massive neuroinflammation are detected. Importantly, the phenotype of both astrocytes and microglia changes in ageing.…”

Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease

“…11,12 Mutant HTT is expressed in glial cells, 13,14 and transgenic mice overexpressing mutant HTT in astrocytes show age-dependent neurological symptoms. 15,16 Additionally, primary astrocytes overexpressing full-length human mutant HTT show reduced mRNA levels of cholesterol biosynthetic genes, along with impaired cellular production and secretion of apoE. 8 Here we employed molecular and cellular tools to test the impact of cholesterol perturbation between astrocytes and neurons in HD.…”