AMPK activation protects from neuronal dysfunction and vulnerability across nematode, cellular and mouse models of Huntington's disease

Rafael P Vázquez-Manrique, Francesca Farina, Karine Cambon, María Dolores Sequedo, Alex J Parker, José María Millán, Andreas Weiss, Nicole Déglon, Christian Neri, Rafael P Vázquez-Manrique, Francesca Farina, Karine Cambon, María Dolores Sequedo, Alex J Parker, José María Millán, Andreas Weiss, Nicole Déglon, Christian Neri

Abstract

The adenosine monophosphate activated kinase protein (AMPK) is an evolutionary-conserved protein important for cell survival and organismal longevity through the modulation of energy homeostasis. Several studies suggested that AMPK activation may improve energy metabolism and protein clearance in the brains of patients with vascular injury or neurodegenerative disease. However, in Huntington's disease (HD), AMPK may be activated in the striatum of HD mice at a late, post-symptomatic phase of the disease, and high-dose regiments of the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide may worsen neuropathological and behavioural phenotypes. Here, we revisited the role of AMPK in HD using models that recapitulate the early features of the disease, including Caenorhabditis elegans neuron dysfunction before cell death and mouse striatal cell vulnerability. Genetic and pharmacological manipulation of aak-2/AMPKα shows that AMPK activation protects C. elegans neurons from the dysfunction induced by human exon-1 huntingtin (Htt) expression, in a daf-16/forkhead box O-dependent manner. Similarly, AMPK activation using genetic manipulation and low-dose metformin treatment protects mouse striatal cells expressing full-length mutant Htt (mHtt), counteracting their vulnerability to stress, with reduction of soluble mHtt levels by metformin and compensation of cytotoxicity by AMPKα1. Furthermore, AMPK protection is active in the mouse brain as delivery of gain-of-function AMPK-γ1 to mouse striata slows down the neurodegenerative effects of mHtt. Collectively, these data highlight the importance of considering the dynamic of HD for assessing the therapeutic potential of stress-response targets in the disease. We postulate that AMPK activation is a compensatory response and valid approach for protecting dysfunctional and vulnerable neurons in HD.

© The Author 2015. Published by Oxford University Press.

Figures

Figure 1.
Figure 1.
aak-2/AMPKα is neuroprotective in 128Q worms. (A) Ablation of the aak-2 gene results in enhancement of the touch phenotype in 128Q worms. (B) Metformin alleviates the touch phenotype of 128Q animals, without affecting the behaviour of 19Q worms. (C) Metformin rescue of the worms depends mostly on the presence of the aak-2 gene. In all panels, values are mean ± SEM (N = 3 with a total of at least 100 animals tested per condition). ANOVA tests, with Tukey post hoc analysis. Ns: not significant. ***P < 0.001.
Figure 2.
Figure 2.
aak-2 requires daf-16 for neuroprotection in a tissue-specific-dependent manner. The deletion of both daf-16 and aak-2 induce a similar enhancement of the touch phenotype. Combining both mutations do not show a synergistic effect, neither an additive effect, suggesting that both genes induce neuroprotecttion though the same pathway. Rescuing aak-2 and daf-16 in mechanosensory neurons rescues the touch phenotype at different levels. Rescue of the touch phenotype by aak-2 overexpression requires daf-16, further suggesting that both work in the same signalling pathway. Values are mean ± SEM (N = 3 with a total of at least 100 animals tested per condition). ANOVA tests, with Tukey post hoc analysis were used. ns: not significant. **P < 0.01 and ***P < 0.001.
Figure 3.
Figure 3.
Nucleo-cytoplasmic expression of AMPKα1 and AMPKα2 in 7Q/7Q and 109Q/109Q mouse striatal cells. (A) RT-PCR analysis of the expression of AMPKα subunits shows that AMPKα1 mRNA levels are higher in 109Q/109Q cells versus 7Q/7Q cells and that AMPKα2 mRNA levels are lower in 109Q/109Q cells versus 7Q/7Q cells. Values are mean ± SD (N = 3 in triplicate). ***P < 0.001. (B) Representative images of antibody staining of both subunits showing that AMPKα1 and AMPKα2 have variable nucleo-cytoplasmic distributions across 7Q/7Q and 109Q/109Q cells. Scale bar is 20 µm. (C) Quantification of nuclear signal intensities for AMPKα1 and AMPKα2 showing that there is more AMPKα1 in 109Q/109Q cells compared with 7Q/7Q cells, which is also observed for AMPKα2. Values are mean ± SEM (N = 3 for a total of at least 90 cells tested per condition). ***P < 0.001. (D) Quantification of nucleo-cytoplasmic distribution for AMPKα1 showing that there is more AMPKα1 in the nucleus of 7Q/7Q cells, which is more pronounced in 109Q/109Q cells. Values are mean ± SEM (N = 3 for a total of at least 90 cells). ***P < 0.001. Statistics were performed using t tests in all panels.
Figure 4.
Figure 4.
Nucleo-cytoplasmic expression of AMPKα-phosphorylated in 7Q/7Q and 109Q/109Q mouse striatal cells. (A) Representative confocal images illustrating that AMPKα-phosphorylated is evenly distributed in the nucleus and cytoplasm in 7Q/7Q and 109Q/109Q cells. Scale bar is 20 µm. (B) The upper two panels show an example of the AMPKα-phosphorylated signal along a line (yellow) that crosses the cytoplasm and nucleus. The blue curve shows DAPI staining, pointing out the region covered by the nuclei, and the green line shows fluorescent due to AMPKα-phosphorylated staining. Colour boxes indicate the area used for the quantification of AMPKα-phosphorylated signals on either side of the nuclear membrane. The lower panel shows the levels of AMPKα-phosphorylated signals, with increase of the signal in both the cytoplasmic and nuclear compartment induced by metformin treatment of 7Q/7Q and 109Q/109Q cells. Values are mean ± SD (N = 3 for a total of at least 50 cells/condition). ANOVA tests, with Tukey post hoc analysis for each genotype, were used. *P < 0.05, **P < 0.01 and ***P < 0.001.
Figure 5.
Figure 5.
AMPK has a protective function in and in vitro model of HD. (A) Growing striatal cells in metformin 2 mm reduces mortality induced by serum deprivation in 109Q/109Q mouse striatal cells (***P < 0.001, N = 3). The right panel shows representative western blots to show that AMPKγ1GOF induces phosphorylation of AMPKα in striatal cells. The levels of Htt do not change. (B) Silencing AMPKα1 by RNAi in 109Q/109Q mouse striatal cells enhances cell mortality in response to serum deprivation with no effect detected in 7Q/7Q cells (***P < 0.001; ns: not significant; N = 3). The right panel shows representative western blots in which AMPKα1 siRNAs reduce AMPKα1 protein levels (N = 3, mean ± SD = 0.4 ± 0.1, P = 0.018) with no change detected in the level of Htt (N = 3, mean ± SD = 1.1 ± 0.5, P = 0.71). (C) Overexpression of an over-activated form of AMPKγ1, AMPKγ1GOF, reduces mortality of 109Q/109Q cells in response to serum deprivation (**P < 0.005, N = 3). The right panel shows representative western blots in which AMPKγ1GOF expression increases AMPKγ1 protein levels (as detected using a c-Myc tag), phosphorylated AMPKα1 levels (N = 3, mean ± SD = 1.6 ± 0.1, P = 0.027). The effect on Htt levels is addressed in (D). (D) Overexpression of the over-activated form of AMPKγ1 induces clearance of misfolded mHtt (***P < 0.001, N = 3). The right panel shows representative western blots in which AMPKγ1GOF increases AMPKγ1 levels (as detected using a c-Myc tag), and phosphorylated AMPKα levels (N = 4, mean ± SD = 1.7 ± 0.4, P = 0.021). In all panels: ns: not significant.
Figure 6.
Figure 6.
In vivo activation of AMPK rescues striatal cell degeneration in a mouse model of HD. (A) Diagram showing the treatment of both sides of the brains of mice with lentiviruses expressing the N-terminal fragment of mHtt [Htt171-82Q (Htt in the diagram)], or the AMPKγ1GOF. Below is shown a representative picture of DARPP32 staining of the sections of the brains of these mice, which highlights the area of the lesion caused by mutant Htt. The right panel shows the analysis of the volume of the lesion caused by mutant Htt, with overexpression of AMPKγ1GOF reducing cell death. Values are mean ± SEM. *P < 0.05 (P = 0.03, N = 13). (B) Representative pictures showing UBI staining and pointing out to inclusion bodies. The right panel shows the quantification of the number of UBI-positive aggregates. Values are mean ± SEM. The overexpression of AMPKγ1GOF does not change the number of inclusion bodies (P = 0.87, N = 13). Statistics use the Wilcoxon test for paired samples. ns: not significant.

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