Mutant Huntingtin Expression Induces Mitochondrial Calcium Handling Defects in Clonal Striatal Cells

Milaković, Tamara Tramišak; Quintanilla, Rodrigo A.; Johnson, Gail V.W.

doi:10.1074/jbc.m603845200

Cited by 123 publications

(151 citation statements)

References 49 publications

(59 reference statements)

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“…These cell lines were a generous gift from Dr. M. E. MacDonald and were prepared from wild-type mice and homozygous Hdh Q111/Q111 knockin mice as described previously (27). Culturing conditions were the same as described in our previous studies (28).…”

Section: Methodsmentioning

confidence: 99%

“…Cells were washed three times and left in KRH-glucose for 10 min until cell fluorescence had equilibrated. Fluorescence was imaged with a confocal laser scanning microscope (Leica TCS SP2) using a 40ϫ water immersion lens, as described previously (28). Images were acquired using a 488-nm Argon laser to excite Fluo-3 fluorescence and a 563 nm He-Ne laser to excite Rhod-2 fluorescence.…”

Section: Methodsmentioning

confidence: 99%

“…The images were analyzed with LCS Leica confocal software and recorded as mean MitoRed or TMRM fluorescence signal per live cell. Estimation of fluorescence intensities were presented as the pseudoratio (⌬F/F o ), which was calculated using the following formula: ⌬F/F o ϭ (F Ϫ F base )/(F base Ϫ B), where F is the measured fluorescence intensity of the indicator, F base is the fluorescence intensity before the stimulation, and B is the background signal determined from the average of areas adjacent to the cells (22,28,30).…”

Section: Methodsmentioning

confidence: 99%

“…Mitochondrial Potential Determination in Live CellsMitochondria membrane potential was determined using Mitotracker Red CM-H 2 XRos (MitoRed) or TMRM (22,28,30). Striatal cells were grown on poly-L-lysine-coated plates and cultured for 4 days.…”

Section: Methodsmentioning

confidence: 99%

“…PPAR␥ activation has been proposed to increase mitochondrial biogenesis in vivo (25), and treatment with PPAR␥ agonists has been proven successful in ameliorating neurodegenerative damage in ischemia and ALS (16,37). Therefore, our aim was to determine if PPAR␥ activation could ameliorate the mutant huntingtin-induced mitochondrial dysfunction observed by our group (6,28) and others (5,26,38). Under basal conditions, mutant cells present with low levels of PPAR␥ expression, in comparison with wild-type cells (Fig.…”

Section: Mutant Huntingtin Expression Significantly Affects the Ppar␥mentioning

confidence: 99%

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Rosiglitazone Treatment Prevents Mitochondrial Dysfunction in Mutant Huntingtin-expressing Cells

Quintanilla

Jin

Fuenzalida

et al. 2008

Journal of Biological Chemistry

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116

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Peroxisome proliferator-activated receptor-␥ (PPAR␥) is a member of the PPAR family of transcription factors. Synthetic PPAR␥ agonists are used as oral anti-hyperglycemic drugs for the treatment of non-insulin-dependent diabetes. However, emerging evidence indicates that PPAR␥ activators can also prevent or attenuate neurodegeneration. Given these previous findings, the focus of this report is on the potential neuroprotective role of PPAR␥ activation in preventing the loss of mitochondrial function in Huntington disease (HD). For these studies we used striatal cells that express wild-type (STHdh Q7/Q7 ) or mutant (STHdh Q111/Q111 ) huntingtin protein at physiological levels. Treatment of mutant cells with thapsigargin resulted in a significant decrease in mitochondrial calcium uptake, an increase in reactive oxygen species production, and a significant decrease in mitochondrial membrane potential. PPAR␥ activation by rosiglitazone prevented the mitochondrial dysfunction and oxidative stress that occurred when mutant striatal cells were challenged with pathological increases in calcium. The beneficial effects of rosiglitazone were likely mediated by activation of PPAR␥, as all protective effects were prevented by the PPAR␥ antagonist GW9662. Additionally, the PPAR␥ signaling pathway was significantly impaired in the mutant striatal cells with decreases in PPAR␥ expression and reduced PPAR␥ transcriptional activity. Treatment with rosiglitazone increased mitochondrial mass levels, suggesting a role for the PPAR␥ pathway in mitochondrial function in striatal cells. Altogether, this evidence indicates that PPAR␥ activation by rosiglitazone attenuates mitochondrial dysfunction in mutant huntingtin-expressing striatal cells, and this could be an important therapeutic avenue to ameliorate the mitochondrial dysfunction that occurs in HD.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Mutant Huntingtin Expression Significantly Affects the Ppar␥mentioning

confidence: 99%

See 3 more Smart Citations

Rosiglitazone Treatment Prevents Mitochondrial Dysfunction in Mutant Huntingtin-expressing Cells

Quintanilla

Jin

Fuenzalida

et al. 2008

Journal of Biological Chemistry

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116

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Mutant huntingtin and glycogen synthase kinase 3‐β accumulate in neuronal lipid rafts of a presymptomatic knock‐in mouse model of Huntington's disease

Valencia

Reeves

Sapp

et al. 2009

J of Neuroscience Research

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Patients with Huntington's disease have an expanded polyglutamine tract in huntingtin and suffer severe brain atrophy and neurodegeneration. Because membrane dysfunction can occur in Huntington's disease, we addressed whether mutant huntingtin in brain and primary neurons is present in lipid rafts, which are cholesterol-enriched membrane domains that mediate growth and survival signals. Biochemical analysis of detergent-resistant membranes from brains and primary neurons of wild-type and presymptomatic Huntington's disease knock-in mice showed that wild-type and mutant huntingtin were recovered in lipid raft-enriched detergent-resistant membranes. The association with lipid rafts was stronger for mutant huntingtin than wild-type huntingtin. Lipid rafts extracted from Huntington's disease mice had normal levels of lipid raft markers (G(alphaq), Ras, and flotillin) but significantly more glycogen synthase kinase 3-beta. Increases in glycogen synthase kinase 3-beta have been associated with apoptotic cell death. Treating Huntington's disease primary neurons with inhibitors of glycogen synthase kinase 3-beta reduced neuronal death. We speculate that accumulation of mutant huntingtin and glycogen synthase kinase 3-beta in lipid rafts of presymptomatic Huntington's disease mouse neurons contributes to neurodegeneration in Huntington's disease.

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Mitochondrial Respiratory Function in Peripheral Blood Cells from Huntington's Disease Patients

Ehinger

Morota

Hansson

et al. 2016

Movement Disord Clin Pract

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Background: Patients with Huntington's disease display symptoms from both the central nervous system and peripheral tissues. Mitochondrial dysfunction has been implicated as part of the pathogenesis of the disease and has been reported in brain tissue and extracerebral tissues, such as muscle and blood cells, but the results are inconsistent. Therefore, the authors performed a refined evaluation of mitochondrial function in 2 types of peripheral blood cells from 14 patients with Huntington's disease and 21 control subjects. Several hypotheses were predefined, including impaired mitochondrial complex II function (primary), complex I function (secondary), and maximum oxidative phosphorylation capacity (secondary) in patient cells. Methods: High-resolution respirometry was applied to viable platelets and mononuclear cells. Data were normalized to cell counts, citrate synthase activity, and mitochondrial DNA copy numbers. Results: Normalized to citrate synthase activity, platelets from patients with Huntington's disease displayed respiratory dysfunction linked to complex I, complex II, and lower maximum oxidative phosphorylation capacity. No difference was seen in mononuclear cells or when platelet data were normalized to cell counts or mitochondrial DNA. The ratio of complex I respiration through maximum oxidative phosphorylation was significantly decreased in patients compared with controls. The corresponding ratio for complex II was unaffected. Conclusions:The data indicate decreased function of mitochondrial complex I in peripheral blood cells from patients with Huntington's disease, although this could not be uniformly confirmed. The results do not confirm a systemic complex II dysfunction and do not currently support the use of mitochondrial function in blood cells as a biomarker for the disease.Huntington's disease (HD) is an autosomal-dominant, progressive, neurodegenerative disease with a phenotype dominated by characteristic chorea, cognitive decline, and psychiatric symptoms. HD is caused by a cytosine-adenine-guanine (CAG) repeat expansion in the huntingtin (HTT) gene, resulting in contiguous glutamine residues and subsequent gain of function in the translated protein.

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Mutant Huntingtin Expression Induces Mitochondrial Calcium Handling Defects in Clonal Striatal Cells

Abstract: Huntington disease (HD) is caused by a pathological elongation of CAG repeats in the huntingtin

Cited by 123 publications

References 49 publications

Rosiglitazone Treatment Prevents Mitochondrial Dysfunction in Mutant Huntingtin-expressing Cells

Rosiglitazone Treatment Prevents Mitochondrial Dysfunction in Mutant Huntingtin-expressing Cells

Mutant huntingtin and glycogen synthase kinase 3‐β accumulate in neuronal lipid rafts of a presymptomatic knock‐in mouse model of Huntington's disease

Mitochondrial Respiratory Function in Peripheral Blood Cells from Huntington's Disease Patients

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