Full-length PGC-1α salvages the phenotype of a mouse model of human neuropathy through mitochondrial proliferation

Róna-Vörös, Krisztina; Eschbach, Judith; Vernay, AurÃ©lia; Wiesner, Diana; Schwalenstöcker, Birgit; Geniquet, Pauline; Camaret, BÃ©nÃ©dicte Mousson De; Echaniz‐Laguna, Andoni; Loeffler, Jean‐Philippe; Ludolph, Albert C.; Weydt, Patrick; Dupuis, Luc

doi:10.1093/hmg/ddt359

Cited by 4 publications

(4 citation statements)

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“…Based on all these, we believe that PGC-1α-deficient mice with a reasonable pathogenic factor and a highly reminiscent phenotype can be a useful animal model for mitochondrial disease, with particular regards to KSS. Though FL-PGC-1α-deficient mice have been not associated with large-scale mtDNA deletions typical of KSS [23], their phenotype is associated with perturbed mtDNA replication (with a decreased mtDNA amount) [38] as well as a globally increased oxidative stress [10], which together may be speculated to be predominantly accounted for the observed CNS phenotype.…”

Section: Discussionmentioning

confidence: 97%

“…One of the two pioneering publications reported the development of a complete (i.e., with no residual expression) PGC-1α whole-body knockout strain, exhibiting hyperactivity with no overt muscle phenotype [14]. Though PGC-1α has recently been demonstrated to have a number of previously unknown isoforms [22], to the current knowledge, this strain can still be regarded as a complete knockout of PGC-1α [23]. Contrastingly, the second pioneering publication reported the development of another whole-body knockout strain demonstrating hypomotility and weakness [15], a strain later turned out to express a functional N-terminal fragment of PGC-1α (NT-PGC-1α) but not the full-length protein (FL-PGC-1α) [24].…”

Section: Highlightsmentioning

confidence: 99%

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Lack of age-related clinical progression in PGC-1α-deficient mice – implications for mitochondrial encephalopathies

Szalárdy

Molnár

Török

et al. 2016

Behavioural Brain Research

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Impaired peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) function has been demonstrated in several neurodegenerative diseases, and murine whole-body knockouts of PGC-1α have been considered as models for Huntington's disease. Recent neuropathological studies, however, rather propose these animals to be morphological models of mitochondrial encephalopathies, with special reminiscence of Kearns-Sayre syndrome. PGC-1α-deficient animals have already been subjected to behavioral assessments; however, the contradictory findings and the paucity of data assessing long-term progression necessitated further examinations. This study provides a comprehensive neurological phenotypic profiling of full-length-(FL-)PGC-1α-deficient mice in a broad age spectrum, with special focus on previously controversial findings, the issue of long-term phenotypic progression, the histopathological assessment of previously non-characterized tissues of potential clinicopathological relevance, and the gene expression profile of novel brain-specific isoforms of PGC-1α. Our findings demonstrate moderate hypomotility with signs of gait and trunk ataxia in addition to severe impairments in coordination and muscle strength in FL-PGC-1α-deficient mice, phenotypic features consistent of a mitochondrial disease. Intriguingly, however, these early alterations did not progress with age, the understanding of which may unveil mechanisms of potential therapeutic relevance, as discussed. The observed phenotype did not associate with retinal or spinal cord alterations, and was accompanied by mild myopathic changes. Based on these, FL-PGC-1α-deficient mice can be regarded not only as morphological but behavioral models of mitochondrial encephalopathies, with an important temporal limitation that has now been clarified. The mechanisms capable of halting a potentially lethal phenotype are to be unveiled, as they may hold therapeutic value for mitochondrial diseases.

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Section: Discussionmentioning

confidence: 97%

Section: Highlightsmentioning

confidence: 99%

Lack of age-related clinical progression in PGC-1α-deficient mice – implications for mitochondrial encephalopathies

Szalárdy

Molnár

Török

et al. 2016

Behavioural Brain Research

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“…Although PGC-1β is non-significantly increased in the SN of PGC1α-KO mice, its expression is reduced when PGC-1α is overexpressed, demonstrating a relationship in the activity of these two transcriptional co-factors (Figure 1 b). PGC-1β is involved in basal mitochondrial biogenesis, whereas the role of PGC-1α is rather to adapt cell metabolic activity, for instance by inducing mitochondrial proliferation in mitochondrial disease [ 43 , 44 ]. Remarkably, myocytes lacking both PGC-1α and β show no difference in mitochondrial content, despite a clear reduction in ETC activity, suggesting that these two parameters are not necessarily coupled, and that PGC-1 activity is primarily involved in adapting oxidative capacity [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

PGC-1α activity in nigral dopamine neurons determines vulnerability to α-synuclein

Ciron

Zheng

Bobela

et al. 2015

acta neuropathol commun

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IntroductionMitochondrial dysfunction and oxidative stress are critical factors in the pathogenesis of age-dependent neurodegenerative diseases. PGC-1α, a master regulator of mitochondrial biogenesis and cellular antioxidant defense, has emerged as a possible therapeutic target for Parkinson’s disease, with important roles in the function and survival of dopaminergic neurons in the substantia nigra. The objective of this study is to determine if the loss of PGC-1α activity contributes to α-synuclein-induced degeneration.ResultsWe explore the vulnerability of PGC-1α null mice to the accumulation of human α-synuclein in nigral neurons, and assess the neuroprotective effect of AAV-mediated PGC-1α expression in this experimental model. Using neuronal cultures derived from these mice, mitochondrial respiration and production of reactive oxygen species are assessed in conditions of human α-synuclein overexpression. We find ultrastructural evidence for abnormal mitochondria and fragmented endoplasmic reticulum in the nigral dopaminergic neurons of PGC-1α null mice. Furthermore, PGC-1α null nigral neurons are more prone to degenerate following overexpression of human α-synuclein, an effect more apparent in male mice. PGC-1α overexpression restores mitochondrial morphology, oxidative stress detoxification and basal respiration, which is consistent with the observed neuroprotection against α-synuclein toxicity in male PGC-1α null mice.ConclusionsAltogether, our results highlight an important role for PGC-1α in controlling the mitochondrial function of nigral neurons accumulating α-synuclein, which may be critical for gender-dependent vulnerability to Parkinson’s disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0200-8) contains supplementary material, which is available to authorized users.

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“…Inducing mitochondrial biogenesis has the potential to improve clinical outcome in a wide array of disorders through a variety of mechanisms, primarily through increasing cellular energy supply and decreasing ROS formation. [7][8][9][10][11][12][13] In many conditions involving mitochondrial dysfunction, impaired ability of the mitochondria to produce ATP is thought to play a major role in disease pathology through the homeostatic stress a diminished energy supply can place on cells in the affected tissues. In several of these conditions, defects or deficiencies in the respiratory chain proteins by way of gene mutations results in decreased ATP production.…”

Section: Mitochondrial Biogenesis and Pgc-1α: Implications In The Trementioning

confidence: 99%

IL-15 Signaling in Skeletal Muscle: Implications in Modulation of PGC-1alpha and Mitochondrial Biogenesis

O’Connell¹

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Proper mitochondrial function is essential in maintaining cellular homeostasis. The mitochondrial network is the primary regulator of cellular metabolism and energy status; disruptions in cellular ATP supply by way of mitochondrial dysfunction severely impairs cell function and as a result plays a central role in the pathogenesis of a wide array of severe neurological, metabolic, and myogenic disorders. Mitochondrial dysfunction, which is characterized by impaired mitochondrial oxidative capacity, has been implicated as a key component in the pathologies of Alzheimer's, Huntington's, Parkinson's, ALS, diabetes, obesity, aging and cancer cachexia. 1-6 Increasing mitochondrial mass by way of mitochondrial biogenesis in conditions of mitochondrial dysfunction has been shown to improve total cellular oxidative capacity and prevent bioenergetic crisis, thus rescuing cellular function, reducing symptom severity, and improving quality of life. 7-14 As a result, there has been a recent push for the development of therapies which stimulate mitochondrial biogenesis by targeting peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a transcriptional coactivator which is known to be one the key regulators of mitochondrial replication. Previously published and preliminary data produced by our laboratory using a transgenic mouse model has provided evidence that altering signaling of the cytokine interleukin 15 (IL-15) by global knockout of one of its key regulatory proteins, interleukin 15 receptor alpha (IL-15Rα), results in potent activation of PGC-1α transcription, significant increases in mitochondrial mass, and improved oxidative capacity in the skeletal muscle of mice. 15,16 Because it is evident that modulating IL-15 and IL-15Rα can elicit dramatic positive mitochondrial changes, determining the specific nature of the changes and the signaling mechanisms responsible provides potential for the development of therapies targeting IL-15 in disease states involving mitochondrial dysfunction. Unfortunately, it is unclear how loss of IL-15Rα affects IL-15 signaling in skeletal

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Full-length PGC-1α salvages the phenotype of a mouse model of human neuropathy through mitochondrial proliferation

Cited by 4 publications

References 50 publications

Lack of age-related clinical progression in PGC-1α-deficient mice – implications for mitochondrial encephalopathies

Lack of age-related clinical progression in PGC-1α-deficient mice – implications for mitochondrial encephalopathies

PGC-1α activity in nigral dopamine neurons determines vulnerability to α-synuclein

IL-15 Signaling in Skeletal Muscle: Implications in Modulation of PGC-1alpha and Mitochondrial Biogenesis

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