Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson’s-like movement disorder

Lu, Wei; Karuppagounder, Senthilkumar S.; Springer, Danielle; Allen, Michele D.; Zheng, Lixin; Chao, Brittany; Zhang, Yan; Dawson, Valina L.; Dawson, Ted M.

doi:10.1038/ncomms5930

Cited by 135 publications

(148 citation statements)

References 51 publications

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“…Unlike our observations in Xenopus development, no significant developmental phenotype has been reported for Pgam5 knockout mice, except for a general reduction in size and body mass, and increased postnatal lethality (Lu et al, 2014;Moriwaki et al, 2016). Interestingly, we also observed increased lethality when higher doses of Pgam5 MO were injected, which might correspond to the observations in Pgam5 knockout mice.…”

Section: Pgam5 Inhibits Recruitment Of Dvl2 To the Tcf1 Complexcontrasting

confidence: 53%

The phosphatase Pgam5 antagonizes Wnt/β-Catenin signaling in embryonic anterior-posterior axis patterning

et al. 2017

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The scaffold protein Dishevelled is a central intracellular component of Wnt signaling pathways. Various kinases have been described that regulate and modulate Wnt signaling through phosphorylation of Dishevelled. However, besides general protein phosphatases 1 and 2 (PP1 and PP2), no specific protein phosphatases have been identified. Here, we report on the identification and functional characterization of the protein phosphatase Pgam5 in vitro and in vivo in Xenopus. Pgam5 is a novel antagonist of Wnt/β-Catenin signaling in human cells and Xenopus embryogenesis. In early development, Pgam5 is essential for head formation, and for establishing and maintaining the Wnt/β-Catenin signaling gradient that patterns the anterior-posterior body axis. Inhibition of Wnt/β-Catenin signaling and developmental function depend on Pgam5 phosphatase activity. We show that Pgam5 interacts with Dishevelled2 and that Dishevelled2 is a substrate of Pgam5. Pgam5 mediates a marked decrease in Dishevelled2 phosphorylation in the cytoplasm and in the nucleus, as well as decreased interaction between Dishevelled2, Tcf1 and β-Catenin, indicating that Pgam5 regulates Dishevelled function upstream and downstream of β-Catenin stabilization.

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Section: Pgam5 Inhibits Recruitment Of Dvl2 To the Tcf1 Complexcontrasting

confidence: 53%

The phosphatase Pgam5 antagonizes Wnt/β-Catenin signaling in embryonic anterior-posterior axis patterning

et al. 2017

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“…Not surprisingly, new evidence show a link between the PGAM/FUNDC1 and the PINK1/ Parkin pathways. Both PINK1 and Parkin are involved in familial Parkinson's disease (14), and PGAM5-deficient mice develop a Parkinson's disease phenotype (57). A recent study discovered that PGAM5 is required for stabilization of PINK1 on damaged mitochondria and that loss of PGAM5 abrogates PINK1-mediated mitophagy (57).…”

Section: Mitochondrial Receptor-mediated Mitophagymentioning

confidence: 99%

“…Both PINK1 and Parkin are involved in familial Parkinson's disease (14), and PGAM5-deficient mice develop a Parkinson's disease phenotype (57). A recent study discovered that PGAM5 is required for stabilization of PINK1 on damaged mitochondria and that loss of PGAM5 abrogates PINK1-mediated mitophagy (57). In addition, both PGAM5 and BNIP3 play roles in hypoxia-mediated mitophagy (8,91), raising the possibility that there is also cooperation between BNIP3 and PGAM5/FUNDC1 in regulating mitochondrial clearance in response to hypoxia.…”

Section: Mitochondrial Receptor-mediated Mitophagymentioning

confidence: 99%

Mending a broken heart: the role of mitophagy in cardioprotection

Moyzis

Sadoshima

Gustafsson

2015

American Journal of Physiology-Heart and Circulatory Physiology

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Moyzis AG, Sadoshima J, Gustafsson ÅB. Mending a broken heart: the role of mitophagy in cardioprotection. Am J Physiol Heart Circ Physiol 308: H183-H192, 2015. First published November 25, 2014 doi:10.1152/ajpheart.00708.2014.-The heart is highly energy dependent with most of its energy provided by mitochondrial oxidative phosphorylation. Mitochondria also play a role in many other essential cellular processes including metabolite synthesis and calcium storage. Therefore, maintaining a functional population of mitochondria is critical for cardiac function. Efficient degradation and replacement of dysfunctional mitochondria ensures cell survival, particularly in terminally differentiated cells such as cardiac myocytes. Mitochondria are eliminated via mitochondrial autophagy or mitophagy. In the heart, mitophagy is an essential housekeeping process and required for cardiac homeostasis. Reduced autophagy and accumulation of impaired mitochondria have been linked to progression of heart failure and aging. In this review, we discuss the pathways that regulate mitophagy in cells and highlight the cardioprotective role of mitophagy in response to stress and aging. We also discuss the therapeutic potential of targeting mitophagy and directions for future investigation.autophagy; mitophagy; mitochondria; parkin; BNIP3; FUNDC1 THE HEART IS HIGHLY ENERGY dependent, and the majority of its energy is provided by mitochondrial oxidative phosphorylation. Mitochondria also play a role in many other cellular processes including metabolite synthesis and calcium storage (41). Hence, maintaining a functional population of mitochondria is critical for cardiac function. Damaged mitochondria produce less ATP, generate greater amounts of reactive oxygen species (ROS), and can activate apoptosis and/or necrosis. Thus efficient removal of dysfunctional mitochondria and biogenesis of functional mitochondria are critical for the maintenance of cellular homeostasis. This is of particular importance in cells such as cardiac myocytes, which are terminally differentiated. The mechanism that the cell uses to eliminate damaged mitochondria is known as mitochondrial autophagy or mitophagy, and involves selective sequestering of the organelle inside an autophagosome and subsequent fusion with a lysosome where degradation occurs (98). Autophagy was initially considered to be a nonselective bulk degradation pathway, especially during stress such as starvation. However, given the critical role of mitochondria in myocytes, it seems unlikely that degradation of mitochondria is a random process, especially during energy deficient conditions such as starvation. This could lead to the degradation of too many mitochondria and compromise cellular survival. A recent study examined changes in the cellular proteome during starvation and found that cytosolic proteins, multiprotein complexes, and organelles show distinct patterns of degradation (46). This study reported that cytosolic proteins are degraded early during starvation, whereas mitochondria are degra...

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“…PINK1 binds to phosphoglycerate mutase family member 5 (PGAM5) in the inner mitochondrial membrane (Lu et al, 2014a) but, upon cleavage, translocates to the cytosol for proteasomal degradation (Fedorowicz et al, 2014;Yamano and Youle, 2013). Upon mitochondrial damage, parkin is recruited to damaged mitochondria downstream of PINK1, which phosphorylates Ser65 on the ubiquitin-like (UBL) domain of parkin (Kondapalli et al, 2012;Shiba-Fukushima et al, 2012) and Ser65 on ubiquitin, leading to parkin activation (Kane et al, 2014;Kazlauskaite et al, 2014;Koyano et al, 2014;Ordureau et al, 2014;Zhang et al, 2014).…”

Section: Dynamics Of Mitochondrial Degradation In Neurodegenerative Dmentioning

confidence: 99%

Autophagosome dynamics in neurodegeneration at a glance

Wong

Holzbaur

2015

Journal of Cell Science

115

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Autophagy is an essential homeostatic process for degrading cellular cargo. Aging organelles and protein aggregates are degraded by the autophagosome-lysosome pathway, which is particularly crucial in neurons. There is increasing evidence implicating defective autophagy in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and Huntington's disease. Recent work using live-cell imaging has identified autophagy as a predominantly polarized process in neuronal axons; autophagosomes preferentially form at the axon tip and undergo retrograde transport back towards the cell body. Autophagosomes engulf cargo including damaged mitochondria (mitophagy) and protein aggregates, and subsequently fuse with lysosomes during axonal transport to effectively degrade their internalized cargo. In this Cell Science at a Glance article and the accompanying poster, we review recent progress on the dynamics of the autophagy pathway in neurons and highlight the defects observed at each step of this pathway during neurodegeneration.

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Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson’s-like movement disorder

Cited by 135 publications

References 51 publications

The phosphatase Pgam5 antagonizes Wnt/β-Catenin signaling in embryonic anterior-posterior axis patterning

The phosphatase Pgam5 antagonizes Wnt/β-Catenin signaling in embryonic anterior-posterior axis patterning

Mending a broken heart: the role of mitophagy in cardioprotection

Autophagosome dynamics in neurodegeneration at a glance

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