ALS-causing mutations differentially affect PGC-1α expression and function in the brain vs. peripheral tissues

Bayer, Hanna; Lang, Kerstin; Buck, Eva; Higelin, Julia; Barteczko, Lara; Pasquarelli, Noemi; Sprissler, Jasmin; Lucas, Tanja; Holzmann, Karlheinz; Demestre, Maria; Lindenberg, Katrin S.; Danzer, Karin M; Boeckers, Tobias M.; Ludolph, Albert C.; Dupuis, Luc; Weydt, Patrick; Witting, Anke

doi:10.1016/j.nbd.2016.11.001

Cited by 40 publications

(38 citation statements)

References 55 publications

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“…Cells were transfected with the renilla containing plasmid for normalization of transfection efficiency and the SIRT3-firefly construct. In addition, different isoforms of PGC-1α on a pCI backbone were added including canonical wt PGC-1α, the brain specific B4-PGC-1α or the brain specific B5-PGC-1α plasmid as described previously (Bayer et al, 2017). The PGC-1α constructs were generously provided by Wolfang Patsch.…”

Section: Methodsmentioning

confidence: 99%

“…Multiple promoters and alternative splicing of the Ppargc1a gene allow for a versatile regulation of the system (Martínez-Redondo et al, 2015). In ALS the situation is particularly complex, as different isoforms are affected differently in different tissues (Bayer et al, 2017). In ALS the canonical and central nervous system (CNS)-specific PGC-1α system is downregulated in disease relevant tissues of the SOD1(G93A) mouse model (Thau et al, 2012; Bayer et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…In ALS the situation is particularly complex, as different isoforms are affected differently in different tissues (Bayer et al, 2017). In ALS the canonical and central nervous system (CNS)-specific PGC-1α system is downregulated in disease relevant tissues of the SOD1(G93A) mouse model (Thau et al, 2012; Bayer et al, 2017). In HD both the canonical and CNS-specific PGC-1α signaling is inhibited (Cui et al, 2006; Weydt et al, 2006; Kim et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…PGC-1α dysfunction also mediates pathological aging (Sahin and DePinho, 2012). In the brain PGC-1α counteracts oxidative stress and protein aggregation (Tsunemi et al, 2012; Bayer et al, 2017). At the transcriptional level PGC-1α regulates the expression of sirtuin 3 (SIRT3), itself an important mitochondrial regulatory protein, via the estrogen related receptor alpha (ERRα; Zhang et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Comparison of Sirtuin 3 Levels in ALS and Huntington’s Disease—Differential Effects in Human Tissue Samples vs. Transgenic Mouse Models

Buck

Bayer

Lindenberg

et al. 2017

Front. Mol. Neurosci.

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Neurodegenerative diseases are characterized by distinct patterns of neuronal loss. In amyotrophic lateral sclerosis (ALS) upper and lower motoneurons degenerate whereas in Huntington’s disease (HD) medium spiny neurons in the striatum are preferentially affected. Despite these differences the pathophysiological mechanisms and risk factors are remarkably similar. In addition, non-neuronal features, such as weight loss implicate a dysregulation in energy metabolism. Mammalian sirtuins, especially the mitochondrial NAD+ dependent sirtuin 3 (SIRT3), regulate mitochondrial function and aging processes. SIRT3 expression depends on the activity of the metabolic master regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a modifier of ALS and HD in patients and model organisms. This prompted us to systematically probe Sirt3 mRNA and protein levels in mouse models of ALS and HD and to correlate these with patient tissue levels. We found a selective reduction of Sirt3 mRNA levels and function in the cervical spinal cord of end-stage ALS mice (superoxide dismutase 1, SOD1G93A). In sharp contrast, a tendency to increased Sirt3 mRNA levels was found in the striatum in HD mice (R6/2). Cultured primary neurons express the highest levels of Sirt3 mRNA. In primary cells from PGC-1α knock-out (KO) mice the Sirt3 mRNA levels were highest in astrocytes. In human post mortem tissue increased mRNA and protein levels of Sirt3 were found in the spinal cord in ALS, while Sirt3 levels were unchanged in the human HD striatum. Based on these findings we conclude that SIRT3 mediates the different effects of PGC-1α during the course of transgenic (tg) ALS and HD and in the human conditions only partial aspects Sirt3 dysregulation manifest.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparison of Sirtuin 3 Levels in ALS and Huntington’s Disease—Differential Effects in Human Tissue Samples vs. Transgenic Mouse Models

Buck

Bayer

Lindenberg

et al. 2017

Front. Mol. Neurosci.

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“…These data suggest that PGC-1α downregulation and α-synuclein oligomerization form a vicious circle (Eschbach et al, 2015). Similarly to PD, certain mutations in amyotrophic lateral sclerosis inhibit the expression of CNS-specific isoforms, indicating this as a common finding in neurodegeneration (Bayer et al, 2017).…”

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confidence: 86%

Effect of MPTP on mRNA expression of PGC-1α in mouse brain

et al. 2017

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The peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC-1α) is a key regulator of mitochondrial biogenesis, respiration and adaptive thermogenesis. Beside the full-length protein (FL-PGC-1α), several other functionally active PGC-1α isoforms were identified as a result of alternative splicing (e.g., N-truncated PGC-1α; NT-PGC-1α) or alternative promoter usage (e.g., central nervous system-specific PGC-1α isoforms; CNS-PGC-1α). The achievement of neuroprotection via the CNS-targeted pharmacological stimulation is limited due to the poor penetration of the blood brain barrier (BBB) by the proposed pharmaceutical agents, so preconditioning emerged as another option. The current study aimed at the examination of how the expression levels of FL-, NT-, CNS-and reference PGC-1α isoforms change in different brain regions following various 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment regimens, including the chronic low dose treatment for preconditioning. Ninety minutes following the acute treatment regimen, the expression level of FL-, NT-and CNS-PGC-1α isoforms increased significantly in the striatum, cortex and cerebellum. However, this elevation was diminished 7 days following the last MPTP injection in this acute treatment regimen. The chronic low dose administration of MPTP, which did not cause significant toxic effect in light of the relatively unaltered dopamine levels, neither resulted in any significant change of PGC-1α expression as well. The elevation of PGC-1α levels following acute treatment may demonstrate a short-term compensatory mechanism against the mitochondrial damage induced by the complex I inhibitor MPTP. However, drug-induced preconditioning by chronic low dose MPTP seems not to induce protective responses via the PGC-1α system.

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From Physiological Properties to Selective Vulnerability of Motor Units in Amyotrophic Lateral Sclerosis

Bączyk¹,

Manuel

Roselli

et al. 2022

Advances in Neurobiology

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ALS-causing mutations differentially affect PGC-1α expression and function in the brain vs. peripheral tissues

Cited by 40 publications

References 55 publications

Comparison of Sirtuin 3 Levels in ALS and Huntington’s Disease—Differential Effects in Human Tissue Samples vs. Transgenic Mouse Models

Comparison of Sirtuin 3 Levels in ALS and Huntington’s Disease—Differential Effects in Human Tissue Samples vs. Transgenic Mouse Models

Effect of MPTP on mRNA expression of PGC-1α in mouse brain

From Physiological Properties to Selective Vulnerability of Motor Units in Amyotrophic Lateral Sclerosis

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