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Neuropeptides. 2016 Aug;58:73-81. doi: 10.1016/j.npep.2016.01.009. Epub 2016 Feb 3.

Insulin and IGF-1 regularize energy metabolites in neural cells expressing full-length mutant huntingtin.

Author information

1
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal; Faculty of Medicine, University of Coimbra, Coimbra 3004-504, Portugal.
2
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal.
3
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal; Institute for Interdisciplinary Research, University of Coimbra (IIIUC), Polo II, Coimbra, Portugal.
4
Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada.
5
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal; Faculty of Medicine, University of Coimbra, Coimbra 3004-504, Portugal. Electronic address: a.cristina.rego@gmail.com.

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder linked to the expression of mutant huntingtin. Bioenergetic dysfunction has been described to contribute to HD pathogenesis. Thus, treatment paradigms aimed to ameliorate energy deficits appear to be suitable candidates in HD. In previous studies, we observed protective effects of insulin growth factor-1 (IGF-1) in YAC128 and R6/2 mice, two HD mouse models, whereas IGF-1 and/or insulin halted mitochondrial-driven oxidative stress in mutant striatal cells and mitochondrial dysfunction in HD human lymphoblasts. Here, we analyzed the effect of IGF-1 versus insulin on energy metabolic parameters using striatal cells derived from HD knock-in mice and primary cortical cultures from YAC128 mice. STHdh(Q111/Q111) cells exhibited decreased ATP/ADP ratio and increased phosphocreatine levels. Moreover, pyruvate levels were increased in mutant cells, most probably in consequence of a decrease in pyruvate dehydrogenase (PDH) protein expression and increased PDH phosphorylation, reflecting its inactivation. Insulin and IGF-1 treatment significantly decreased phosphocreatine levels, whereas IGF-1 only decreased pyruvate levels in mutant cells. In a different scenario, primary cortical cultures derived from YAC128 mice also displayed energetic abnormalities. We observed a decrease in both ATP/ADP and phosphocreatine levels, which were prevented following exposure to insulin or IGF-1. Furthermore, decreased lactate levels in YAC128 cultures occurred concomitantly with a decline in lactate dehydrogenase activity, which was ameliorated with both insulin and IGF-1. These data demonstrate differential HD-associated metabolic dysfunction in striatal cell lines and primary cortical cultures, both of which being alleviated by insulin and IGF-1.

KEYWORDS:

Energy metabolism; Huntington's disease; IGF-1; Insulin; Lactate; Lactate dehydrogenase; Pyruvate dehydrogenase

PMID:
26876526
DOI:
10.1016/j.npep.2016.01.009
[Indexed for MEDLINE]

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