The Role of PGC-1α in the Pathogenesis of Neurodegenerative Disorders

Róna-Vörös, Krisztina; Weydt, Patrick

doi:10.2174/1389210205941754501

Cited by 12 publications

(15 citation statements)

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“…PGC-1α is a nuclear-encoded protein that plays important roles in the transcriptional regulation of mitochondrial function at several levels, including mitochondrial biogenesis, glucose and lipid metabolism as well as oxidative stress defence, and its dysfunction has been implicated in the pathogenesis of a number of neurodegenerative diseases both in humans and experimental animals [37,43]. FL-PGC-1α-deficient mice develop liver disease, decreased locomotion and muscle weakness [23], together with a spongiform leukoencephalopathy with wide-spread vacuolation accompanied by reactive astrogliosis in the brainstem and the cerebellar nuclei, resembling the neuropathological alterations seen in KSS [43].…”

Section: Communicating Authormentioning

confidence: 99%

Histopathological comparison of Kearns-Sayre syndrome and PGC-1α-deficient mice suggests a novel concept for vacuole formation in mitochondrial encephalopathy

Szalárdy

Molnár

Török

et al. 2016

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A b s t r a c t Despite the current hypotheses about myelinic and astrocytic ion-dyshomeostasis underlying white (WM) and grey matter (GM) vacuolation in mitochondrial encephalopathies, there is a paucity of data on the exact mechanism of vacuole formation. To revisit the concepts of vacuole formation associated with mitochondrial dysfunction, we performed a comparative neuropathological analysis in Kearns-Sayre syndrome (KSS) and full-length peroxisome proliferator-activated receptor-g coactivator-1α (FL-PGC-1α)-deficient mice, a recently proposed morphological model of mitochondrial encephalopathies. Brain tissues from an individual with genetically proven KSS (22-year-old man) and aged

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Section: Communicating Authormentioning

confidence: 99%

Histopathological comparison of Kearns-Sayre syndrome and PGC-1α-deficient mice suggests a novel concept for vacuole formation in mitochondrial encephalopathy

Szalárdy

Molnár

Török

et al. 2016

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“…The role of PGC-1a system in neurodegenerative disorders including HD has been reported both in human patients and in animal models (Chaturvedi et al, 2009(Chaturvedi et al, , 2010Kim et al 2010;Rona-Voros and Weydt 2010;Johri et al 2013). HD is an inherited neurodegenerative disease caused by the expansion of CAG trinucleotide repeat that encodes the polyglutamine region in the huntingtin protein.…”

Section: Introductionmentioning

confidence: 99%

mRNA Expression Levels of PGC-1α in a Transgenic and a Toxin Model of Huntington’s Disease

et al. 2014

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Peroxisome Proliferator-Activated Receptor-Gamma (PPARγ) Coactivator-1 Alpha is involved in the regulation of mitochondrial biogenesis, respiration and adaptive thermogenesis. The full-length PGC-1α (FL-PGC-1α) comprises multiple functional domains interacting with several transcriptional regulatory factors such as nuclear respiratory factors, estrogen-related receptors and PPARs; however, a number of PGC-1α splice variants have also been reported recently. In this study, we examined the expression levels of FL-PGC-1αand N-truncated PGC-1α (NT-PGC-1α), a shorter but functionally active splice variant of PGC-1α protein, in N171-82Q transgenic and 3-nitropropionic acid-induced murine model of Huntington's disease (HD). The expression levels were determined by RT-PCR in three brain areas (striatum, cortex and cerebellum) in three age groups (8, 12 and 16 weeks). Besides recapitulating prior findings that NT-PGC-1α is preferentially increased in 16 weeks of age in transgenic HD animals, we detected age-dependent alterations in both models, including a cerebellum-predominant upregulation of both PGC-1α variants in transgenic mice, and a striatum-predominant upregulation of both PGC-1α variants after acute 3-nitropropionic acid intoxication. The possible relevance of this expression pattern is discussed. Based on our results, we assume that increased expression of PGC-1α may serve as a compensatory mechanism in response to mitochondrial damage in transgenic and toxin models of HD, which may be of therapeutic relevance.

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“…PPAR-γ-coactivator 1alpha (PGC1-alpha) induces gene expression that promotes differentiation, and increases fatty acid oxidation via expansion of mitochondrial capacity and function (177). PGC1alpha binds to nuclear PPAR- The relevance of these data to AD is that genetic deficiencies in PGC1 alpha increase proneness to neurodegeneration (179,180). This suggests that PGC1 alpha may represent an excellent therapeutic target for AD, and possibly other major neurodegenerative diseases as well.…”

Section: Insulin Sensitizers-peroxisome Proliferator-activated Receptmentioning

confidence: 99%

“…In essence, PGC1alpha is an important negative regulator of oxidative stress, mitochondrial dysfunction, lipotoxicity, and insulin resistance (177)(178)(179). The relevance of these data to AD is that genetic deficiencies in PGC1 alpha increase proneness to neurodegeneration (179,180). This suggests that PGC1 alpha may represent an excellent therapeutic target for AD, and possibly other major neurodegenerative diseases as well.…”

Section: Insulin Sensitizers-peroxisomementioning

confidence: 99%

Therapeutic targets of brain insulin resistance in sporadic Alzheimer s disease

Monte

2012

Front Biosci

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Growing evidence supports roles for brain insulin and insulin-like growth factor (IGF) resistance and metabolic dysfunction in the pathogenesis of Alzheimer's disease (AD). Whether the underlying problem stems from a primary disorder of central nervous system (CNS) neurons and glia, or secondary effects of systemic diseases such as obesity, Type 2 diabetes, or metabolic syndrome, the end-results include impaired glucose utilization, mitochondrial dysfunction, increased oxidative stress, neuroinflammation, and the propagation of cascades that result in the accumulation of neurotoxic misfolded, aggregated, and ubiquitinated fibrillar proteins. This article reviews the roles of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism, and discusses therapeutic strategies and lifestyle approaches that could be used to prevent, delay the onset, or reduce the severity of AD. Finally, it is critical to recognize that AD is heterogeneous and has a clinical course that fully develops over a period of several decades. Therefore, early and multi-modal preventive and treatment approaches should be regarded as essential. KeywordsAmyloid; Anti-oxidants; Brain diabetes; Brain insulin resistance; Incretins; Insulin; Insulin sensitizers; Liver-Brain-Axis; Metal Chelation; Neuroprotection; Nitrosamine; Oxidative Stress; Polyphenols; Statins; Streptozotocin; Tau; Type 3 diabetes INTRODUCTIONThe gold standard for definitively diagnosing AD is to perform a postmortem examination of the brain, with the objective of demonstrating beyond-normal aging associated densities of neurofibrillary tangles, neuritic plaques, and amyloid-beta 40-42 kD fragments of amyloid beta precursor protein (AβPP-Aβ) deposits in corticolimbic structures, bearing in mind that neurodegeneration frequently involves multiple other cortical regions as well. The common thread among these characteristic lesions is that they harbor insoluble aggregates of abnormally phosphorylated and ubiquitinated tau, and neurotoxic AβPP-Aβ in the form of Send correspondence to: Suzanne M. de la Monte, Rhode Island Hospital, 55 Claverick Street, Room 419, Providence, RI. 02903, Tel: 401-444-7364, Fax: 401-444-2939, Suzanne_DeLaMonte_MD@Brown.edu. HHS Public Access Author manuscriptFront Biosci (Elite Ed). Author manuscript; available in PMC 2015 August 26. Published in final edited form as:Front Biosci (Elite Ed). ; 4: 1582-1605. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript oligomers, fibrillar aggregates, or extracellular plaques. Secreted AβPP-Aβ oligomers have been demonstrated to be neurotoxic and to inhibit hippocampal long-term potentiation, i.e. synaptic plasticity (1).To improve diagnosis and treatment, we must learn to connect the development and progression of neurodegeneration with molecular, biochemical, physiological, neuroimaging, and clinical abnormalities in AD. Several strategies could be taken to advance this proc...

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The Role of PGC-1α in the Pathogenesis of Neurodegenerative Disorders

Cited by 12 publications

References 0 publications

Histopathological comparison of Kearns-Sayre syndrome and PGC-1α-deficient mice suggests a novel concept for vacuole formation in mitochondrial encephalopathy

Histopathological comparison of Kearns-Sayre syndrome and PGC-1α-deficient mice suggests a novel concept for vacuole formation in mitochondrial encephalopathy

mRNA Expression Levels of PGC-1α in a Transgenic and a Toxin Model of Huntington’s Disease

Therapeutic targets of brain insulin resistance in sporadic Alzheimer s disease

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