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

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/AMPK? 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 AMPK?1. Furthermore, AMPK protection is active in the mouse brain as delivery of gain-of-function AMPK-?1 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.

SUBMITTER: Vazquez-Manrique RP

PROVIDER: S-EPMC4764188 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Vázquez-Manrique Rafael P RP Farina Francesca F Cambon Karine K Dolores Sequedo María M Parker Alex J AJ Millán José María JM Weiss Andreas A Déglon Nicole N Neri Christian C

Human molecular genetics 20151217 6

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 ...[more]

PMID: 26681807

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Project description:BackgroundSpinal muscular atrophy (SMA) is a form of motor neuron disease affecting primarily children characterised by the loss of lower motor neurons (MNs). Breakdown of the neuromuscular junctions (NMJs) is an early pathological event in SMA. However, not all motor neurons are equally vulnerable, with some populations being lost early in the disease while others remain intact at the disease end-stage. A thorough understanding of the basis of this selective vulnerability will give critical insight into the factors which prohibit pathology in certain motor neuron populations and consequently help identify novel neuroprotective strategies.MethodsTo retrieve a comprehensive understanding of motor neuron susceptibility in SMA, we mapped NMJ pathology in 20 muscles from the Smn2B/- SMA mouse model and cross-compared these data with published data from three other commonly used mouse models. To gain insight into the molecular mechanisms regulating selective resilience and vulnerability, we analysed published RNA sequencing data acquired from differentially vulnerable motor neurons from two different SMA mouse models.ResultsIn the Smn2B/- mouse model of SMA, we identified substantial NMJ loss in the muscles from the core, neck, proximal hind limbs and proximal forelimbs, with a marked reduction in denervation in the distal limbs and head. Motor neuron cell body loss was greater at T5 and T11 compared with L5. We subsequently show that although widespread denervation is observed in each SMA mouse model (with the notable exception of the Taiwanese model), all models have a distinct pattern of selective vulnerability. A comparison of previously published data sets reveals novel transcripts upregulated with a disease in selectively resistant motor neurons, including genes involved in axonal transport, RNA processing and mitochondrial bioenergetics.ConclusionsOur work demonstrates that the Smn2B/- mouse model shows a pattern of selective vulnerability which bears resemblance to the regional pathology observed in SMA patients. We found drastic differences in patterns of selective vulnerability across the four SMA mouse models, which is critical to consider during experimental design. We also identified transcript groups that potentially contribute to the protection of certain motor neurons in SMA mouse models.

Project description:Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin protein. Neuropathology in the basal ganglia and in the cerebral cortex has been linked to the motor and cognitive symptoms whereas recent work has suggested that the hypothalamus might be involved in the metabolic dysfunction. Several mouse models of HD that display metabolic dysfunction have hypothalamic pathology, and expression of mutant huntingtin in the hypothalamus has been causally linked to the development of metabolic dysfunction in mice. Although the pathogenic mechanisms by which mutant huntingtin exerts its toxic functions in the HD brain are not fully known, several studies have implicated a role for the lysososomal degradation pathway of autophagy. Interestingly, changes in autophagy in the hypothalamus have been associated with the development of metabolic dysfunction in wild-type mice. We hypothesized that expression of mutant huntingtin might lead to changes in the autophagy pathway in the hypothalamus in mice with metabolic dysfunction. We therefore investigated whether there were changes in basal levels of autophagy in a mouse model expressing a fragment of 853 amino acids of mutant huntingtin selectively in the hypothalamus using a recombinant adeno-associate viral vector approach as well as in the transgenic BACHD mice. We performed qRT-PCR and Western blot to investigate the mRNA and protein expression levels of selected autophagy markers. Our results show that basal levels of autophagy are maintained in the hypothalamus despite the presence of metabolic dysfunction in both mouse models. Furthermore, although there were no major changes in autophagy in the striatum and cortex of BACHD mice, we detected modest, but significant differences in levels of some markers in mice at 12 months of age. Taken together, our results indicate that overexpression of mutant huntingtin in mice do not significantly perturb basal levels of autophagy.

Project description:Huntington's disease (HD) is an inherited, relentlessly progressive neurodegenerative disease with an invariably fatal outcome. HD is inherited in an autosomal dominant fashion, and is characterized pathologically by the loss of cortical and striatal neurons, and clinically by involuntary choreiform movements accompanied by progressive cognitive impairment and emotional lability. The disorder is caused by an expanded cystosine adenine guanine (CAG) tri-nucleotide repeat encoding polyglutamine (polyQ) in the first exon of the Huntingtin gene. There is a correlation between the number of CAG repeats and disease onset, such that in patients with CAG repeat lengths of 36 to 60, disease symptoms typically manifest after 35 years of age, whereas CAG repeat lengths >60 yield the more severe juvenile form of the disease. Even though mutant huntingtin is expressed throughout the brain, it is characterized by the selective degeneration of medium spiny neurons of the caudate and putamen, which heralds more widespread neuronal degeneration with disease progression. The mechanisms of cell dysfunction and death in HD have been the subjects of a number of studies, which have led to therapeutic strategies largely based on the amelioration of mutant huntingtin-related metabolic impairment and cellular toxicity. Each of these approaches has aimed to delay or stop the preferential degeneration of medium spiny neurons early in the disease course. Yet, in later stages of the disease, after cell death has become prominent, cell replacement therapy (whether by direct cell transplantation or by the mobilization of endogenous progenitors) may comprise a stronger potential avenue for therapy. In this review, we will consider recent progress in the transplantation of fetal striatal cells to the HD brain, as well as emerging alternative sources for human striatal progenitor cells. We will then consider the potential application of gene therapy toward the induction of striatal neurogenesis and neuronal recruitment, with an eye toward its potential therapeutic use in HD.

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

Publications

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

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