Molecular Pathophysiological Mechanisms in Huntington’s Disease (original) (raw)
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Human molecular genetics, 2018
Neuronal and non-neuronal cells express the huntingtin protein, yet neurodegeneration in Huntington's Disease (HD) is largely selective, affecting most prominently striatal medium spiny neurons and cortical pyramidal neurons. Selective toxicity of full-length mutant huntingtin (fl-mHTT) may be due in part to its expression in non-neuronal cells. While studies suggest neuronal-glial interactions are important in HD and fl-mHTT is expressed in astrocytes, it has not been determined whether the expression of fl-mHTT in astrocytes is necessary for HD pathogenesis. To directly assess the necessity of fl-mHTT in astrocytes for HD pathogenesis, we used a mouse genetic approach and bred the conditional mutant huntingtin expressing BACHD mouse model with GFAP-CreERT2 mice. We show that GFAP-CreERT2 expression in these mice is highly selective for astrocytes and we are able to significantly reduce the expression of fl-mHTT protein in the striatum and cortex of BACHD/GFAP-CreERT2-tam mice....
Loss of normal huntingtin function: new developments in Huntington's disease research
Trends in Neurosciences, 2001
Huntington's disease (HD) with the discovery that the disease-causing mutation is the expansion of a variable stretch of CAG triplets (to more than the maximum 35 repeats normally present) in the first exon of the HD gene 1 , which encodes a widely expressed 348 kDa cytoplasmic protein named huntingtin 1 . CAG translates into glutamine (gln), and the resulting mutant huntingtin protein is therefore characterized by an aberrant poly-gln expansion. As a consequence of the presence of this expanded protein, the striatal medium-sized spiny neurons undergo selective degeneration accompanied in HD by progressive chorea and dementia 2 .
Nature Medicine, 2014
Huntington's disease (HD) is a fatal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion leading to an elongated polyglutamine stretch in Huntingtin 1. Mutant Huntingtin (mHTT) is ubiquitously expressed but elicits selective cortical and striatal neurodegeneration in HD 2. The mechanistic basis for such selective neuronal vulnerability remains unclear. A necessary step towards resolving this enigma is to define the cell types in which mHTT expression is causally linked to the disease pathogenesis. Using a conditional human Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
HUNTINGTON'S DISEASE: UNDERSTANDING THE PATHOPHYSIOLOGY THROUGH THE HUNTINGTIN GENE
Huntington's Disease (HD) is a progressive neurodegenerative disorder. It is an autosomal dominant disorder that is categorized by motor dysfunctions, behavioral and cognitive deficits. Reason for this disease is expansion of the polyglutamine (due to the more CAG repeat) in the amino-terminal region of the exon 1 of the Huntingtin gene (HTT). Furthermore, the mutant HTT gene is occupied in the HD associated changes of neurotransmission for enabling the neurodegeneration. Even though the the important pathophysiology of the HD happens in the caudate and putamen, rest regions of the brain are similarly influenced and also show a significant characteristic in the HD pathophysiology. Until now actual remedy for the HD is not available. As a result, current approaches are directing to the HTT gene expression silencing. It is now taken as the probable way of the management of HD. But the most important thing is, core functions of the HTT gene in the brain of adult subject are presently not clear at all and henceforward the outcome of the continued HTT gene expression suppression of is unpredictable. It could be possibly being tough. This review is based on the pathophysiology of HTT on HD.
Mutant Huntingtin in Glial Cells Exacerbates Neurological Symptoms of Huntington Disease Mice
Journal of Biological Chemistry, 2010
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 (
Mechanisms of neurodegeneration in Huntington’s disease
European Journal of Neuroscience, 2008
Huntington’s disease (HD) is caused by an expansion of cytosine–adenine–guanine (CAG) repeats in the huntingtin gene, which leads to neuronal loss in the striatum and cortex and to the appearance of neuronal intranuclear inclusions of mutant huntingtin. Huntingtin plays a role in protein trafficking, vesicle transport, postsynaptic signaling, transcriptional regulation, and apoptosis. Thus, a loss of function of the normal protein and a toxic gain of function of the mutant huntingtin contribute to the disruption of multiple intracellular pathways. Furthermore, excitotoxicity, dopamine toxicity, metabolic impairment, mitochondrial dysfunction, oxidative stress, apoptosis, and autophagy have been implicated in the progressive degeneration observed in HD. Nevertheless, despite the efforts of a multidisciplinary scientific community, there is no cure for this devastating neurodegenerative disorder. This review presents an overview of the mechanisms that may contribute for HD pathogenesi...
Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity
The Journal of Cell Biology, 2005
Huntington disease (HD) is characterized by the preferential loss of striatal medium-sized spiny neurons (MSNs) in the brain. Because MSNs receive abundant glutamatergic input, their vulnerability to excitotoxicity may be largely influenced by the capacity of glial cells to remove extracellular glutamate. However, little is known about the role of glia in HD neuropathology. Here, we report that mutant huntingtin accumulates in glial nuclei in HD brains and decreases the expression of glutamate transporters. As a result, mutant huntingtin (htt) reduces glutamate uptake in cultured astrocytes and HD mouse brains. In a neuron–glia coculture system, wild-type glial cells protected neurons against mutant htt-mediated neurotoxicity, whereas glial cells expressing mutant htt increased neuronal vulnerability. Mutant htt in cultured astrocytes decreased their protection of neurons against glutamate excitotoxicity. These findings suggest that decreased glutamate uptake caused by glial mutant ...
Human Molecular Genetics, 2007
To test the hypotheses that mutant huntingtin protein length and wild-type huntingtin dosage have important effects on disease-related transcriptional dysfunction, we compared the changes in mRNA in seven genetic mouse models of Huntington's disease (HD) and postmortem human HD caudate. Transgenic models expressing short N-terminal fragments of mutant huntingtin (R6/1 and R6/2 mice) exhibited the most rapid effects on gene expression, consistent with previous studies. Although changes in the brains of knock-in and fulllength transgenic models of HD took longer to appear, 15-and 22-month CHL2 Q150/Q150 , 18-month Hdh Q92/Q92 and 2-year-old YAC128 animals also exhibited significant HD-like mRNA signatures. Whereas it was expected Downloaded from that the expression of full-length huntingtin transprotein might result in unique gene expression changes compared with those caused by the expression of an N-terminal huntingtin fragment, no discernable differences between full-length and fragment models were detected. In addition, very high correlations between the signatures of mice expressing normal levels of wild-type huntingtin and mice in which the wild-type protein is absent suggest a limited effect of the wild-type protein to change basal gene expression or to influence the qualitative disease-related effect of mutant huntingtin. The combined analysis of mouse and human HD transcriptomes provides important temporal and mechanistic insights into the process by which mutant huntingtin kills striatal neurons. In addition, the discovery that several available lines of HD mice faithfully recapitulate the gene expression signature of the human disorder provides a novel aspect of validation with respect to their use in preclinical therapeutic trials.
Neuron, 1999
We have produced yeast artificial chromosome (YAC) transgenic mice expressing normal (YAC18) and mutant (YAC46 and YAC72) huntingtin (htt) in a developmental and tissue-specific manner identical to that observed in Huntington's disease (HD). YAC46 and YAC72 mice show early electrophysiological abnormalities, indicating cytoplasmic dysfunction prior to observed nuclear inclusions or neurodegeneration. By 12 months of age, YAC72 mice have a selective degeneration of medium spiny neurons in the lateral striatum associated with the translocation of N-terminal htt fragments to the nucleus. Neurodegeneration can be present in the absence of macro- or microaggregates, clearly showing that aggregates are not essential to initiation of neuronal death. These mice demonstrate that initial neuronal cytoplasmic toxicity is followed by cleavage of htt, nuclear translocation of htt N-terminal fragments, and selective neurodegeneration.
A Fresh Look at Huntingtin mRNA Processing in Huntington’s Disease
Journal of Huntington's Disease, 2018
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a mutation that expands the polyglutamine (CAG) repeat in exon 1 of the huntingtin (HTT) gene. Wild-type HTT protein interacts with other proteins to protect cells against toxic stimuli, mediate vesicle transport and endocytosis, and modulate synaptic activity. Mutant HTT protein disrupts autophagy, vesicle transport, neurotransmitter signaling, and mitochondrial function. Although many of the activities of wild-type HTT protein and the toxicities of mutant HTT protein are characterized, less is known about the activities of HTT mRNA. Most putative HD therapies aim to target mutant HTT mRNA before it is translated into the protein. Therefore, it is imperative to learn as much as we can about how cells handle both wild-type and mutant HTT mRNA so that effective therapies can be designed. Here, we review the structure of wild-type and mutant HTT mRNA, with emphasis on their alternatively polyadenylated or spliced isoforms. We then consider the abundance of HTT mRNA isoforms in HD and discuss the potential implications of these findings. Evidence in the review should be used to guide future research aimed at developing mRNA-lowering therapies for HD.