Browsing by Author "Johnson, Gail V. W."

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    Phosphorylated tau potentiates Aβ-induced mitochondrial damage in mature neurons
    (2014) Quintanilla, Rodrigo A.; von Bernhardi, Rommy; Godoy, Juan A.; Inestrosa, Nibaldo C.; Johnson, Gail V. W.
    Tau phosphorylated at the PHF-1 epitope (S396/S404) is likely involved in the pathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms by which tau phosphorylated at these sites negatively impacts neuronal functions are still under scrutiny. Previously, we showed that expression of tau truncated at D421 enhances mitochondrial dysfunction induced by A beta in cortical neurons. To extend these findings, we expressed tau pseudo-phosphorylated at S396/404 (T42EC) in mature and young cortical neurons and evaluated different aspects of mitochondrial function in response to A beta. Expression of T42EC did not induce significant changes in mitochondrial morphology, mitochondrial length, or mitochondrial transport, compared to GFP and full-length tau. However, T42EC expression enhanced A beta-induced mitochondrial membrane potential loss and increased superoxide levels compared to what was observed in mature neurons expressing full-length tau. The same effect was observed in mature neurons that expressed both pseudo-phosphorylated and truncated tau when they were treated with AS. Interestingly, the mitochondrial failure induced by A beta in mature neurons that expressed T42EC, was not observed in young neurons expressing T42EC. These novel findings suggest that phosphorylated tau (PHF-1 epitope) enhances A beta-induced mitochondrial injury, which contributes to neuronal dysfunction and to the pathogenesis of AD. (C) 2014 Elsevier Inc All rights reserved.
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    Rosiglitazone treatment prevents mitochondrial dysfunction in mutant huntingtin-expressing cells -: Possible role of peroxisome proliferator-activated receptor-γ (PPARγ) in the pathogenesis of Huntington disease
    (2008) Quintanilla, Rodrigo A.; Jin, Youngnam N.; Fuenzalida, Karen; Bronfman, Miguel; Johnson, Gail V. W.
    Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a member of the PPAR family of transcription factors. Synthetic PPAR gamma agonists are used as oral anti-hyperglycemic drugs for the treatment of non-insulin-dependent diabetes. However, emerging evidence indicates that PPAR gamma activators can also prevent or attenuate neurodegeneration. Given these previous findings, the focus of this report is on the potential neuroprotective role of PPAR gamma 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 gamma 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 gamma, as all protective effects were prevented by the PPAR gamma antagonist GW9662. Additionally, the PPAR gamma signaling pathway was significantly impaired in the mutant striatal cells with decreases in PPAR gamma expression and reduced PPAR gamma transcriptional activity. Treatment with rosiglitazone increased mitochondrial mass levels, suggesting a role for the PPAR gamma pathway in mitochondrial function in striatal cells. Altogether, this evidence indicates that PPAR gamma 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.