Mutant Huntingtin in Glial Cells Exacerbates Neurological Symptoms of Huntington Disease Mice

Abstract

Huntington disease (HD) is caused by an expansion of the polyglutamine (polyQ) repeat (>37Q) in huntingtin (htt), and age of onset is inversely correlated with the length of the polyQ repeat. Mutant htt with expanded polyQ is ubiquitously expressed in various types of cells, including glia, but causes selective neurodegeneration. Our recent study demonstrated that expression of the N-terminal mutant htt with a large polyQ repeat (160Q) in astrocytes is sufficient to induce neurological symptoms in mice (Bradford, J., Shin, J. Y., Roberts, M., Wang, C. E., Li, X.-J., and Li, S. H. (2009) Proc. Natl. Acad. Sci. U.S.A. 106, 22480 -22485). Because glia-neuron interactions are critical for maintaining the normal function and survival of neurons in the brain and because mutant htt is more abundant in neurons than in glial cells, it is important to investigate whether glial htt can still contribute to HD pathology when mutant htt is abundantly expressed in neuronal cells. We generated transgenic mice that express mutant htt with 98Q in astrocytes. Unlike our recently generated htt-160Q transgenic mice, htt-98Q mice do not show obvious neurological phenotypes, suggesting that the length of the polyQ repeat determines the severity of glial dysfunction. However, htt-98Q mice show increased susceptibility to glutamate-induced seizure. Mice expressing mutant htt in astrocytes were mated with N171-82Q mice that express mutant htt primarily in neuronal cells. Double transgenic mice expressing mutant htt in both neuronal and glial cells display more severe neurological symptoms and earlier death than N171-82Q mice. These findings indicate a role of glial mutant htt in exacerbating HD neuropathology and underscore the importance of improving glial function in treating HD. Huntington disease (HD)3 is an inherited neurological disorder caused by a polyglutamine (polyQ) expansion in huntingtin (htt). The polyQ expansion is also the common genetic mutation for eight other neurodegenerative diseases including spinal cerebellar ataxia 1-3, 6, 7, 17. A noticeable pathology feature of these diseases is that the mutant proteins, which are ubiquitously expressed in the body and brain, cause selective neurodegeneration in distinct brain regions in each disease (1). In HD, selective neuronal loss preferentially occurs in the striatum, the deep layers of the cerebral cortex and extends to many other brain regions during the late stage of the disease (2). This phenomenon has led to extensive studies of the effects of mutant htt in neuronal cells. Several HD transgenic mouse models have been generated including those expressing mutant htt under the endogenous htt promoter (knock-in), transgenic human htt promoters (YAC, BAC, and R6/2), or the mouse neuronal prion promoter (N171-82Q) (3). Mice expressing truncated htt (R6/2 and N171-82Q) show more severe phenotypes than YAC or BAC transgenic mice that express fulllength mutant htt (3, 4), suggesting that N-terminal mutant htt is more pathogenic than full-length mutant htt. In addition to the p...

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

“…30 Impairments in astrocytic function are increasingly recognized as a culprit in neuronal dysfunction in neurodegenerative diseases, 31 such as amyotrophic lateral sclerosis, 32 Rett's syndrome, 33,34 lysosomal disorders, 35 Alzheimer's disease, 36 and HD. 16 Accordingly, astrocyte kir4.1 ion channel deficits contribute to neuronal dysfunction in Figure 4b is the same. See Supplementary Figure 9 for full-length pictures of the blots shown in b, e, and f Figure 4 Genetic modulation of SREBP2 in astrocytes influences neurite outgrowth in HD neurons.…”

“…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.…”

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

“…First, compared with glial cells, lower and impaired neuronal ubiquitin-proteasome system activity, which plays a critical role in clearing misfolded proteins [18] , may account for the preferential accumulation of misfolded Htt in neurons as well as their selective vulnerability [19][20][21] . Second, the expression of mutant huntingtin in glial cells, which could clear excess excitatory neurotransmitters from extracellular space, contributed to neuronal excitotoxicity [2,5,22,23] .…”

“…On the membranes of astrocytes, which are the major subtype of glial cells, there are two types of glutamate transporters (GLT-1 and GLAST) that do most of the work in clearing extracellular excitatory neurotransmitters [7,8] . It has been shown that small fragments of N-terminal mutant Htt (such as N-208, N-171), which were reported to be more pathogenic than full-length mutant Htt, caused decreased expression of GLT-1 [2,5] . However, these fragments had been cut occasionally and might not exist in physiological and pathological conditions, so they could not simulate the condition of HD patients completely.…”

“…These studies indicate that cell-cell interactions between neurons and glial cells play an important role in HD pathology [3,4] . In addition, mutant Htt expressed in glial cells could exacerbate neurological symptoms in HD transgenic mice, so the role of glial cells in HD neuropathology should not be neglected [5] .…”