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In JoVE (1)
Other Publications (6)
Articles by Stephan J. Guyenet in JoVE
A Simple Composite Phenotype Scoring System for Evaluating Mouse Models of Cerebellar Ataxia
Stephan J. Guyenet1, Stephanie A. Furrer2, Vincent M. Damian1, Travis D. Baughan2, Albert R. La Spada*3, Gwenn A. Garden*2
1Department of Biochemistry, University of Washington, 2Department of Neurology, University of Washington, 3Division of Genetics, Departments of Pediatrics and Cellular and Molecular Medicine, and the Institute for Genomic Medicine, University of California, San Diego - Rady Children’s Hospital
We describe a protocol for the rapid and sensitive quantification of disease severity in mouse models of cerebellar ataxia. Measures include hind limb clasping, ledge test, gait and kyphosis. This protocol effectively discriminates between affected and non-affected individuals, and detects the progression of affected individuals over time.
Other articles by Stephan J. Guyenet on PubMed
Bergmann Glia Expression of Polyglutamine-expanded Ataxin-7 Produces Neurodegeneration by Impairing Glutamate Transport
Nature Neuroscience. Oct, 2006 | Pubmed ID: 16936724
Non-neuronal cells may be pivotal in neurodegenerative disease, but the mechanistic basis of this effect remains ill-defined. In the polyglutamine disease spinocerebellar ataxia type 7 (SCA7), Purkinje cells undergo non-cell-autonomous degeneration in transgenic mice. We considered the possibility that glial dysfunction leads to Purkinje cell degeneration, and generated mice that express ataxin-7 in Bergmann glia of the cerebellum with the Gfa2 promoter. Bergmann glia-specific expression of mutant ataxin-7 was sufficient to produce ataxia and neurodegeneration. Expression of the Bergmann glia-specific glutamate transporter GLAST was reduced in Gfa2-SCA7 mice and was associated with impaired glutamate transport in cultured Bergmann glia, cerebellar slices and cerebellar synaptosomes. Ultrastructural analysis of Purkinje cells revealed findings of dark cell degeneration consistent with excitotoxic injury. Our studies indicate that impairment of glutamate transport secondary to glial dysfunction contributes to SCA7 neurodegeneration, and suggest a similar role for glial dysfunction in other polyglutamine diseases and SCAs.
Posttranslational Modification of Ataxin-7 at Lysine 257 Prevents Autophagy-mediated Turnover of an N-terminal Caspase-7 Cleavage Fragment
The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Dec, 2009 | Pubmed ID: 19955365
Polyglutamine (polyQ) expansion within the ataxin-7 protein, a member of the STAGA [SPT3-TAF(II)31-GCN5L acetylase] and TFTC (GCN5 and TRRAP) chromatin remodeling complexes, causes the neurodegenerative disease spinocerebellar ataxia type 7 (SCA7). Proteolytic processing of ataxin-7 by caspase-7 generates N-terminal toxic polyQ-containing fragments that accumulate with disease progression and play an important role in SCA7 pathogenesis. To elucidate the basis for the toxicity of these fragments, we evaluated which posttranslational modifications of the N-terminal fragment of ataxin-7 modulate turnover and toxicity. Here, we show that mutating lysine 257 (K257), an amino acid adjacent to the caspase-7 cleavage site of ataxin-7 regulates turnover of the truncation product in a repeat-dependent manner. Modification of ataxin-7 K257 by acetylation promotes accumulation of the fragment, while unmodified ataxin-7 is degraded. The degradation of the caspase-7 cleavage product is mediated by macroautophagy in cell culture and primary neuron models of SCA7. Consistent with this, the fragment colocalizes with autophagic vesicle markers, and enhanced fragment accumulation increases in these lysosomal structures. We suggest that the levels of fragment accumulation within the cell is a key event in SCA7 neurodegeneration, and enhancing clearance of polyQ-containing fragments may be an effective target to reduce neurotoxicity in SCA7.
Diabetes. Dec, 2010 | Pubmed ID: 21115781
The Journal of Clinical Investigation. Jan, 2012 | Pubmed ID: 22201683
Rodent models of obesity induced by consuming high-fat diet (HFD) are characterized by inflammation both in peripheral tissues and in hypothalamic areas critical for energy homeostasis. Here we report that unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain. Furthermore, both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding. Although these responses temporarily subsided, suggesting that neuroprotective mechanisms may initially limit the damage, with continued HFD feeding, inflammation and gliosis returned permanently to the mediobasal hypothalamus. Consistent with these data in rodents, we found evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI. These findings collectively suggest that, in both humans and rodent models, obesity is associated with neuronal injury in a brain area crucial for body weight control.
Regulation of Food Intake, Energy Balance, and Body Fat Mass: Implications for the Pathogenesis and Treatment of Obesity
The Journal of Clinical Endocrinology and Metabolism. Jan, 2012 | Pubmed ID: 22238401
Context:Obesity has emerged as one of the leading medical challenges of the 21st century. The resistance of this disorder to effective, long-term treatment can be traced to the fact that body fat stores are subject to homeostatic regulation in obese individuals, just as in lean individuals. Because the growing obesity epidemic is linked to a substantial increase in daily energy intake, a key priority is to delineate how mechanisms governing food intake and body fat content are altered in an obesogenic environment.Evidence Acquisition:We considered all relevant published research and cited references that represented the highest quality evidence available. Where space permitted, primary references were cited.Evidence Synthesis:The increase of energy intake that has fueled the U.S. obesity epidemic is linked to greater availability of highly rewarding/palatable and energy-dense food. Obesity occurs in genetically susceptible individuals and involves the biological defense of an elevated body fat mass, which may result in part from interactions between brain reward and homeostatic circuits. Inflammatory signaling, accumulation of lipid metabolites, or other mechanisms that impair hypothalamic neurons may also contribute to the development of obesity and offer a plausible mechanism to explain the biological defense of elevated body fat mass.Conclusions:Despite steady research progress, mechanisms underlying the resistance to fat loss once obesity is established remain incompletely understood. Breakthroughs in this area may be required for the development of effective new obesity prevention and treatment strategies.