Gastrodia elata prevents huntingtin aggregations through activation of the adenosine A2A receptor and ubiquitin proteasome system

Huang, Chuen Lin; Yang, Jung Mou; Wang, Kaw Chen; Lee, Yi Chao; Lin, Yun; Yang, Ying; Huang, Nai Kuei

doi:10.1016/j.jep.2011.08.075

Cited by 36 publications

(14 citation statements)

References 26 publications

(30 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5 to 8). Reagents that activate the cAMP/PKA pathway in the striatum are therefore beneficial in HD mice, as was reported previously (11,20,34). This cross talk between PKA and the proteasome might be brain area specific or disease stage dependent.…”

Section: Discussionsupporting

confidence: 53%

Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease

Lin

Chang

Chen

et al. 2013

Molecular and Cellular Biology

View full text Add to dashboard Cite

Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a CAG repeat in the Huntingtin (HTT) gene. Abnormal regulation of the cyclic AMP (cAMP)/protein kinase A (PKA) pathway occurs during HD progression. Here we found that lower PKA activity was associated with proteasome impairment in the striatum for two HD mouse models (R6/2 and N171-82Q) and in mutant HTT (mHTT)-expressing striatal cells. Because PKA regulatory subunits (PKA-Rs) are proteasome substrates, the mHTT-evoked proteasome impairment caused accumulation of PKA-Rs and subsequently inhibited PKA activity. Conversely, activation of PKA enhanced the phosphorylation of Rpt6 (a component of the proteasome), rescued the impaired proteasome activity, and reduced mHTT aggregates. The dominant-negative Rpt6 mutant (Rpt6 S120A ) blocked the ability of a cAMP-elevating reagent to enhance proteasome activity, whereas the phosphomimetic Rpt6 mutant (Rpt6 S120D ) increased proteasome activity, reduced HTT aggregates, and ameliorated motor impairment. Collectively, our data demonstrated that positive feedback regulation between PKA and the proteasome is critical for HD pathogenesis. Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by expansion of a CAG repeat in the Huntingtin (HTT) gene. The normal HTT gene has 35 or fewer CAG repeats in its N-terminal region, whereas expansion of the repeat beyond 35 units confers toxicity to the Huntingtin protein (HTT) and evokes HD pathogenesis (1). The major clinical presentations of HD include chorea, cognitive decline, psychiatric symptoms, and a systemic metabolic defect (2). Selective neuronal loss occurs in multiple brain regions, particularly in the striatum and cortex. Since a great number of cellular machineries (including transcription, vesicle transport, molecular chaperones, and the ubiquitin-proteasome system [UPS]) are compromised by the expression of mutant HTT (mHTT) (3), effective removal of mHTT has become one of the most challenging aspects of drug development for HD.The UPS, which degrades misfolded and/or damaged proteins in eukaryotes, is the major regulatory proteolytic pathway. It regulates many essential cellular processes, including transcription, translation, DNA repair, chromatin remodeling, cell survival, signal transduction, protein trafficking, and synaptic plasticity (4). A recent study demonstrated that AAA-ATPase subunits are critical for cell-type-specific regulation of UPS activity (5). Interestingly, UPS activity is under metabolic control. Posttranslational modifications, such as O-GlcNacylation and phosphorylation of 19S subunits, affect the proteolytic activity of the UPS (6). In addition, impaired functioning of the UPS is believed to contribute to the pathogenic processes of many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease (PD), and HD. Recent studies revealed that the UPS might be impaired in HD mouse models and patients (7,8). Intriguingly, although the degradation of polyubiquitin-tagg...

show abstract

Section: Discussionsupporting

confidence: 53%

Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease

Lin

Chang

Chen

et al. 2013

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…Rat PC12 cells purchased from American Type Culture Collection (ATCC; Manassas, VA, USA) were maintained in DMEM supplemented with 10% horse serum and 5% FBS and incubated in a CO 2 incubator (5%) at 37°C. pHtt-25Q-mKate and pHtt-109Q-mKate were prepared as described previously [55].…”

Section: Methodsmentioning

confidence: 99%

When Cytokinin, a Plant Hormone, Meets the Adenosine A2A Receptor: A Novel Neuroprotectant and Lead for Treating Neurodegenerative Disorders?

et al. 2012

Self Cite

View full text Add to dashboard Cite

It is well known that cytokinins are a class of phytohormones that promote cell division in plant roots and shoots. However, their targets, biological functions, and implications in mammalian systems have rarely been examined. In this study, we show that one cytokinin, zeatin riboside, can prevent pheochromocytoma (PC12) cells from serum deprivation-induced apoptosis by acting on the adenosine A2A receptor (A2A-R), which was blocked by an A2A-R antagonist and a protein kinase A (PKA) inhibitor, demonstrating the functional ability of zeatin riboside by mediating through A2A-R signaling event. Since the A2A-R was implicated as a therapeutic target in treating Huntington’s disease (HD), a cellular model of HD was applied by transfecting mutant huntingtin in PC12 cells. By using filter retardation assay and confocal microscopy we found that zeatin riboside reversed mutant huntingtin (Htt)-induced protein aggregations and proteasome deactivation through A2A-R signaling. PKA inhibitor blocked zeatin riboside-induced suppression of mutant Htt aggregations. In addition, PKA activated proteasome activity and reduced mutant Htt protein aggregations. However, a proteasome inhibitor blocked both zeatin riboside-and PKA activator-mediated suppression of mutant Htt aggregations, confirming mediation of the A2A-R/PKA/proteasome pathway. Taken together, zeatin riboside might have therapeutic potential as a novel neuroprotectant and a lead for treating neurodegenerative disorders.

show abstract

“…Likewise, other manipulations also indicate that A 2A R activation might be neuroprotective (Huang et al . ; Mievis et al . ).…”

Section: The Role Of A2ar In Neuroprotectionmentioning

confidence: 99%

How does adenosine control neuronal dysfunction and neurodegeneration?

Cunha

2016

Journal of Neurochemistry

368

385

View full text Add to dashboard Cite

The adenosine modulation system mostly operates through inhibitory A 1 (A 1 R) and facilitatory A 2A receptors (A 2A R) in the brain. The activity-dependent release of adenosine acts as a brake of excitatory transmission through A 1 R, which are enriched in glutamatergic terminals. Adenosine sharpens salience of information encoding in neuronal circuits: highfrequency stimulation triggers ATP release in the 'activated' synapse, which is locally converted by ecto-nucleotidases into adenosine to selectively activate A 2A R; A 2A R switch off A 1 R and CB1 receptors, bolster glutamate release and NMDA receptors to assist increasing synaptic plasticity in the 'activated' synapse; the parallel engagement of the astrocytic syncytium releases adenosine further inhibiting neighboring synapses, thus sharpening the encoded plastic change. Brain insults trigger a large outflow of adenosine and ATP, as a danger signal. A 1 R are a hurdle for damage initiation, but they desensitize upon prolonged activation. However, if the insult is near-threshold and/or of short-duration, A 1 R trigger preconditioning, which may limit the spread of damage. Brain insults also up-regulate A 2A R, probably to bolster adaptive changes, but this heightens brain damage since A 2A R blockade affords neuroprotection in models of epilepsy, depression, Alzheimer's, or Parkinson's disease. This initially involves a control of synaptotoxicity by neuronal A 2A R, whereas astrocytic and microglia A 2A R might control the spread of damage. The A 2A R signaling mechanisms are largely unknown since A 2A R are pleiotropic, coupling to different G proteins and non-canonical pathways to control the viability of glutamatergic synapses, neuroinflammation, mitochondria function, and cytoskeleton dynamics. Thus, simultaneously bolstering A 1 R preconditioning and preventing excessive A 2A R function might afford maximal neuroprotection. Keywords: A 1 receptor, A 2A receptor, astrocyte, microglia, synaptic plasticity, synaptotoxicity. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases". Relevance of modulation systems to tune information flow in brain circuitsThe goal of understanding the flow of information in neuronal circuits has traditionally been centered in studying the key processes sustaining synaptic transmission and plasticity -i.e. the role of glutamate and glutamate receptors, as well as to a lesser extent the role of GABA and its receptors. If one considers an analogy to the experience of watching TV, this corresponds to studying how the ON/OFF button impacts all Received April 4, 2016; revised manuscript received May 23, 2016; accepted June 23, 2016. Address correspondence and reprint requests to R. A. Cunha, Center for Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal. E-mail: cunharod@gmail.com Abbreviations used: A 1 R, adenosine A 1 receptor; A 2A R, adenosine A 2A receptor; ADHD, attention deficit and hyperactivity disorder; BDNF, brain-derived neurotrophi...

show abstract

Gastrodia elata prevents huntingtin aggregations through activation of the adenosine A2A receptor and ubiquitin proteasome system

Cited by 36 publications

References 26 publications

Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease

Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease

When Cytokinin, a Plant Hormone, Meets the Adenosine A2A Receptor: A Novel Neuroprotectant and Lead for Treating Neurodegenerative Disorders?

How does adenosine control neuronal dysfunction and neurodegeneration?

Contact Info

Product

Resources

About