Adult Conditional Knockout of PGC-1α Leads to Loss of Dopamine Neurons

Jiang, Hongzhi; Kang, Sung Ung; Zhang, Shuran; Karuppagounder, Senthilkumar S.; Xu, Jinling; Lee, Yong Kyu; Kang, Bong Gu; Zhang, Jianmin; Pletniková, Olga; Troncoso, Juan C.; Pirooznia, Shelia; Andrabi, Shaida A.; Dawson, Valina L.; Dawson, Ted M.

doi:10.1523/eneuro.0183-16.2016

Cited by 89 publications

(64 citation statements)

References 30 publications

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“…PGC-1α activation of NRF1 leads to transcription of nuclear-encoded mitochondrial genes and of the mitochondrial DNA transcriptional factor Tfam, which activates transcription and replication of the mitochondrial genome, thereby controlling mitochondrial biogenesis ( Gleyzer et al, 2005 ; Koopman et al, 2010 ; Scarpulla et al, 2012 ; Ventura-Clapier et al, 2008 ). PGC-1α dysregulation and impaired mitochondrial biogenesis have been implicated in neurodegenerative disorders ( Calkins et al, 2011 ; Coppola et al, 2009 ; García-Giménez et al, 2011 ; Jiang et al, 2016 ; Johri et al, 2013 ; Marmolino et al, 2010 ; McGill and Beal, 2006 ; Reddy et al, 2012 ; Ruiz et al, 2012 ; Sandi et al, 2014 ; Shin et al, 2011 ; Stevens et al, 2015 ; Thau et al, 2012 ). Downregulation of PGC-1α mRNA and protein have been reported in skeletal muscle, fibroblasts and neural precursor cells cultured from FRDA patients and animal models ( Coppola et al, 2009 ; Marmolino et al, 2010 ; Sandi et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia

Lin

Magrané

Rattelle

et al. 2017

Disease Models &Amp; Mechanisms

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Friedreich ataxia (FRDA), the most common recessive inherited ataxia, results from deficiency of frataxin, a small mitochondrial protein crucial for iron-sulphur cluster formation and ATP production. Frataxin deficiency is associated with mitochondrial dysfunction in FRDA patients and animal models; however, early mitochondrial pathology in FRDA cerebellum remains elusive. Using frataxin knock-in/knockout (KIKO) mice and KIKO mice carrying the mitoDendra transgene, we show early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in this FRDA model. At asymptomatic stages, the levels of PGC-1α (PPARGC1A), the mitochondrial biogenesis master regulator, are significantly decreased in cerebellar homogenates of KIKO mice compared with age-matched controls. Similarly, the levels of the PGC-1α downstream effectors, NRF1 and Tfam, are significantly decreased, suggesting early impaired cerebellar mitochondrial biogenesis pathways. Early mitochondrial deficiency is further supported by significant reduction of the mitochondrial markers GRP75 (HSPA9) and mitofusin-1 in the cerebellar cortex. Moreover, the numbers of Dendra-labeled mitochondria are significantly decreased in cerebellar cortex, confirming asymptomatic cerebellar mitochondrial biogenesis deficits. Functionally, complex I and II enzyme activities are significantly reduced in isolated mitochondria and tissue homogenates from asymptomatic KIKO cerebella. Structurally, levels of the complex I core subunit NUDFB8 and complex II subunits SDHA and SDHB are significantly lower than those in age-matched controls. These results demonstrate complex I and II deficiency in KIKO cerebellum, consistent with defects identified in FRDA patient tissues. Thus, our findings identify early cerebellar mitochondrial biogenesis deficits as a potential mediator of cerebellar dysfunction and ataxia, thereby providing a potential therapeutic target for early intervention of FRDA.

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Section: Discussionmentioning

confidence: 99%

Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia

Lin

Magrané

Rattelle

et al. 2017

Disease Models &Amp; Mechanisms

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“…Recent evidence has demonstrated that adult conditional PGC-1α KO mice display a significant loss of DA neurons in the SNpc (Jiang et al, 2016). Taken together with PGC-1α overexpression data, which has been shown to rescue mitochondrial biogenesis defects and accompanying neurodegeneration, it stands to reason that finding compounds which upregulate PGC-1α expression may be therapeutically beneficial.…”

Section: Therapeuticsmentioning

confidence: 99%

Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes

Scott

Dawson

2017

Experimental Neurology

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Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons. Most PD cases are sporadic; however, rare familial forms have been identified. Autosomal recessive PD (ARPD) results from mutations in Parkin, PINK1, DJ-1, and ATP13A2, while rare, atypical juvenile ARPD result from mutations in FBXO7, DNAJC6, SYNJ1, and PLA2G6. Studying these genes and their function has revealed mitochondrial quality control, protein degradation processes, and oxidative stress responses as common pathways underlying PD pathogenesis. Understanding how aberrancy in these common processes leads to neurodegeneration has provided the field with numerous targets that may be therapeutically relevant to the development of disease-modifying treatments.

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“…PARIS (ZNF746) is a pathologic parkin substrate, which is increased in sporadic and familial PD brains and is responsible for DA neuronal loss in mouse models of parkin inactivation (Shin et al, 2011; Siddiqui et al, 2015; Siddiqui et al, 2016; Stevens et al, 2015). PARIS accumulation represses the transcriptional coactivator, peroxisome proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α), which is critical for DA neuron survival (Ciron et al, 2015; Jiang et al, 2016; Mudo et al, 2012; Zheng et al, 2010). …”

Section: Introductionmentioning

confidence: 99%

PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival

et al. 2017

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Mutations in PTEN-induced putative kinase 1 (PINK1) and parkin cause autosomal-recessive Parkinson’s disease through a common pathway involving mitochondrial quality control. Parkin inactivation leads to accumulation of the parkin interacting substrate (PARIS, ZNF746) that plays an important role in dopamine cell loss through repression of proliferator-activated receptor gamma coactivator-1α (PGC-1α) promoter activity. Here we show that PARIS, links PINK1 and parkin in a common pathway that regulates dopaminergic neuron survival. PINK1 interacts with and phosphorylates serines 322 and 613 of PARIS to control its ubiquitination and clearance by parkin. PINK1 phosphorylation of PARIS alleviates PARIS toxicity as well as repression of PGC-1α promoter activity. Conditional knockdown of PINK1 in adult mouse brains leads to a progressive loss of dopaminergic neurons in the substantia nigra that is dependent on PARIS. Together, these results uncover a function of PINK1 to direct parkin-PARIS regulated PGC-1α expression and dopaminergic neuronal survival.

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Adult Conditional Knockout of PGC-1α Leads to Loss of Dopamine Neurons

Cited by 89 publications

References 30 publications

Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia

Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia

Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes

PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival

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