PGC-1α, mitochondrial dysfunction, and Huntington's disease

doi:10.1016/j.freeradbiomed.2013.04.016

Free Radical Biology and Medicine

Volume 62, September 2013, Pages 37-46

https://doi.org/10.1016/j.freeradbiomed.2013.04.016 Get rights and content

Highlights

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PGC-1α function/expression is impaired in HD.
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PGC-1α plays a crucial role in mitochondrial biogenesis and antioxidant defense.
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Mitochondrial dysfunction and oxidative damage are consistently observed in HD.
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Therapeutic approaches targeting PGC-1α have great promise for HD.

Abstract

The constant high energy demand of neurons makes them rely heavily on their mitochondria. Dysfunction of mitochondrial energy metabolism leads to reduced ATP production, impaired calcium buffering, and generation of reactive oxygen species. There is strong evidence that mitochondrial dysfunction results in neurodegeneration and may contribute to the pathogenesis of Huntington's disease (HD). Studies over the past few years have implicated an impaired function of peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), a transcriptional master coregulator of mitochondrial biogenesis, metabolism, and antioxidant defenses, in causing mitochondrial dysfunction in HD. Here we have attempted to discuss in a nutshell, the key findings on the role of PGC-1α in mitochondrial dysfunction in HD and its potential as a therapeutic target to cure HD.

Graphical abstract

Various ways PGC-1α can impact Huntington's disease.

Introduction

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by the expansion of a CAG repeat in the gene encoding the protein huntingtin, leading to expression of mutant huntingtin with expanded polyglutamine repeats [1]. The expansion of polyglutamine repeats results in acquisition of an altered conformation by mutant huntingtin, which in turn causes the protein to aggregate. The function of normal huntingtin protein has not been fully elucidated yet, but it is known to be associated with synaptic vesicles and microtubules, and is an essential scaffold protein regulating axonal transport of vesicles including brain-derived neurotrophic factor (BDNF) [2], [3], [4], [5], [6], [7]. The huntingtin protein was recently shown to play a role linking the glycolytic enzyme GAPDH to vesicles, to supply energy from glycolysis for fast axonal transport [8]. Both a gain-of-function (for mutant huntingtin) hypothesis and a loss-of-function (for normal huntingtin) hypothesis have been put forward to explain HD pathogenesis. Patients with HD have CAG repeat lengths above 36, with variable penetrance of repeat lengths 36–39 and complete penetrance above 39 repeats; longer repeat lengths (>60) have been associated with juvenile-onset HD [9]. Disease manifestations can begin at any time in life; the most common age range of onset is between 30 and 50 years old, although it occurs in children and the elderly as well. The juvenile variant of HD usually results from paternal transmission and is associated with increased severity as well as with a more rapid progression of the disease.

HD is characterized by progressive motor impairment, personality changes, psychiatric illness, and gradual intellectual decline. Pathologically, there is a preferential and progressive loss of the medium spiny neurons (MSNs) in the striatum, as well as cortical atrophy, and degeneration of other brain regions later in the disease. There are no currently available treatments to delay disease onset or retard its progression, and the focus of medical care is limited to symptom management and maximizing function. Transcriptional dysregulation, protein aggregation, mitochondrial dysfunction, and enhanced oxidative stress have been implicated in the disease pathogenesis. A key feature of HD patients is pronounced weight loss, despite sustained caloric intake. Deficits in energy expenditure have been linked with mitochondrial dysfunction in HD. The evidence for mitochondrial dysfunction in HD has been reviewed earlier [10], [11], [12]; we have summarized a few key findings in the following discussion.

Section snippets

Mitochondrial dysfunction in HD

There is extensive evidence for bioenergetic deficits and mitochondrial dysfunction in HD, such as a pronounced weight loss despite sustained caloric intake, nuclear magnetic resonance spectroscopy showing increased lactate in the cerebral cortex and basal ganglia, decreased activities of oxidative phosphorylation (OXPHOS) complexes II and III, and reduced aconitase activity in the basal ganglia, abnormal mitochondrial membrane depolarization in patient lymphoblasts, abnormal ultrastructure of

Oxidative damage in HD

Mitochondria are both targets and important sources of ROS. Increased levels of ROS including superoxide (O₂^•–), hydrogen peroxide (H₂O₂), hydroxyl radical (^•OH), and reactive nitrogen species such as peroxynitrite (ONOO⁻) impair cellular function by degrading proteins, lipids, and nucleic acids. It has been shown that oxidative stress stimulates mitochondrial fission; the addition of hydrogen peroxide to cultured cerebellar granule neurons induced mitochondrial fragmentation within one hour of

PGC-1α: The master coactivator

Peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1 (PGC-1) family of coactivators is an extensively regulated group of proteins that are highly responsive to a variety of environmental cues, from temperature to nutritional status, to physical activity. This family of coactivators plays a crucial role in integrating signaling pathways, tailoring them to best suit the changing cellular and systemic milieu. The first and perhaps the best studied member of the PGC-1 family of

Functional consequences of impaired PGC-1α activity in HD

In recent years, impaired PGC-1α expression and/or function has emerged as a common underlying cause of mitochondrial dysfunction in HD. There is substantial evidence for impairment of PGC-1α levels and activity in HD [23], [73], [74], [75], [76]. Involvement of PGC-1α in HD was first suggested by the findings that PGC-1α knockout mice exhibit mitochondrial dysfunction, defective bioenergetics, a hyperkinetic movement disorder, and striatal degeneration, which are features also observed in HD

PGC-1α and PPARs

PGC-1α is now increasingly being recognized as an important therapeutic target for HD. As discussed above, there is a plethora of evidence for impaired PGC-1α expression and/or function in HD; therefore pharmacologic/transcriptional activation of PGC-1α pathway is expected to have neuroprotective effects. Indeed, overexpression of PGC-1α was shown to enhance the mitochondrial membrane potential and to reduce mitochondrial toxicity in in vitro models of HD [74]. Lentiviral delivery of PGC-1α to

Conclusions and therapeutic implications

There is now incontrovertible evidence that a deficiency of PGC-1α plays a role in the pathogenesis of HD. There are reduced levels of PGC-1α mRNA in striated cell lines with mutant huntingtin, transgenic mouse models of HD, and HD postmortem brain tissue. Furthermore one study showed that 24/26 PGC-1α-coactivated genes were reduced in expression in HD postmortem brain tissue. The impairment of PGC-1α expression appears to be due to mutant huntingtin-mediated interference with

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Review ArticlePGC-1α, mitochondrial dysfunction, and Huntington's disease

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Mitochondrial dysfunction in HD

Oxidative damage in HD

PGC-1α: The master coactivator

Functional consequences of impaired PGC-1α activity in HD

PGC-1α and PPARs

Conclusions and therapeutic implications

Neuron

Exp. Neurol.

Trends Cell. Biol.

Neuron

Cell

Cell

J. Biol. Chem.

Trends Neurosci.

Brain Res. Rev.

J. Biol. Chem.

Free Radic. Biol. Med.

Biochem. Biophys. Res. Commun.

Neuroscience

Free Radic. Biol. Med.

J. Biol. Chem.

Neuron

Mol. Cell. Proteomics

DNA Repair (Amst.)

Free Radic. Biol. Med.

Free Radic. Biol. Med.

J. Biol. Chem.

Cell

Cell

Cell Metab.

J. Biol. Chem.

Cell

Cell

Cell Metab.

Cell

Psychiatry Res.

Lancet Neurol.

Neuroimage

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group

Cell

Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons

EMBO J.

Huntington disease

J. Neuropathol. Exp. Neurol.

Mitochondrial dysfunction in neurodegenerative diseases

J. Pharmacol. Exp. Ther.

The energetics of Huntington's disease

Neurochem. Res.

Energy deficit in Huntington disease: why it matters

J. Clin. Invest.

HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism

Hum. Mol. Genet

Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release

Hum. Mol. Genet

Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines

Nat. Neurosci.

N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking

J. Neurosci.

Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid

J. Neurosci.

Impaired brain creatine kinase activity in Huntington's disease

Neurodegener. Dis.

Mitochondrial loss, dysfunction and altered dynamics in Huntington's disease

Hum. Mol. Genet

Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington's disease

Hum. Mol. Genet

Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity

Nat. Med

Review Article
PGC-1α, mitochondrial dysfunction, and Huntington's disease