BCAT-induced autophagy regulates Aβ load through an interdependence of redox state and PKC phosphorylation-implications in Alzheimer's disease

Harris, Michael A.; Hindy, Maya El; Moraes, Marcela Usmari; Hudd, Fred; Shafei, Mai Ahmed; Dong, Ming; Hezwani, Mohammed; Clark, Paul A.; House, Michael J.; Forshaw, Tom E.; Kehoe, Patrick Gavin; Conway, Myra E.

doi:10.1016/j.freeradbiomed.2020.01.019

Cited by 15 publications

(15 citation statements)

References 72 publications

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“…BCAT was identified as a novel chaperone in protein folding through its thiol oxidoreductase activity, El Hindy et al 2014). Our most recent study offers evidence that these 'moonlighting' functions are fundamental in regulating autophagy and play a fundamental role in regulating Ab (Harris et al 2020). Here, BCATc-mediated autophagy was shown to be regulated through PKC-mediated phosphorylation, modulated by the redox state of BCATc.…”

Section: Moonlighting Roles For Bcatmentioning

confidence: 93%

Alzheimer’s disease: targeting the glutamatergic system

Conway

2020

Biogerontology

129

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BCATc Cytosolic BCAT BCATm Mitochondrial BCAT BCKA Branched chain a-keto acids BCKD Branched chain a-keto acid dehydrogenase Cho Choline Cr Creatinine Glu Glutamate Glx Glu?glutamine GDH Glutamate dehydrogenase MSUD Maple syrup urine disease NAA N-acetyl aspartate NMDAR N-methyl-D-aspartate receptor NFTs Neurofibrillary tangles PLP Pyridoxal phosphate PSEN1 Presenilin 1 1 H MRS Proton magnetic resonance spectroscopy mI Myoinositol TBI Traumatic brain injury

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Section: Moonlighting Roles For Bcatmentioning

confidence: 93%

Alzheimer’s disease: targeting the glutamatergic system

Conway

2020

Biogerontology

129

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“…BCAT isoforms are redox-sensitive proteins and are in their reduced form part of a metabolon with glutamate dehydrogenase (GDH) catalyzing the conversion of glutamate into α-ketoglutarate (Conway et al, 2002(Conway et al, , 2004(Conway et al, , 2008). An increase in oxidative stress (OS) might change the redox status, preventing this metabolon formation (Harris et al, 2020). The reduced glutamate and aspartate total amounts observed in AD neurons may be due to changes in the redox state of BCAT, causing reduced amino acid synthesis.…”

Section: Bcaa Metabolism In Admentioning

confidence: 99%

Functional Metabolic Mapping Reveals Highly Active Branched-Chain Amino Acid Metabolism in Human Astrocytes, Which Is Impaired in iPSC-Derived Astrocytes in Alzheimer's Disease

Salcedo

Andersen

Vinten

et al. 2021

Front. Aging Neurosci.

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The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are important nitrogen donors for synthesis of glutamate, the main excitatory neurotransmitter in the brain. The glutamate carbon skeleton originates from the tricarboxylic acid (TCA) cycle intermediate α-ketoglutarate, while the amino group is derived from nitrogen donors such as the BCAAs. Disturbances in neurotransmitter homeostasis, mainly of glutamate, are strongly implicated in the pathophysiology of Alzheimer's disease (AD). The divergent BCAA metabolism in different cell types of the human brain is poorly understood, and so is the involvement of astrocytic and neuronal BCAA metabolism in AD. The goal of this study is to provide the first functional characterization of BCAA metabolism in human brain tissue and to investigate BCAA metabolism in AD pathophysiology using astrocytes and neurons derived from human-induced pluripotent stem cells (hiPSCs). Mapping of BCAA metabolism was performed using mass spectrometry and enriched [15N] and [13C] isotopes of leucine, isoleucine, and valine in acutely isolated slices of surgically resected cerebral cortical tissue from human brain and in hiPSC-derived brain cells carrying mutations in either amyloid precursor protein (APP) or presenilin-1 (PSEN-1). We revealed that both human astrocytes of acutely isolated cerebral cortical slices and hiPSC-derived astrocytes were capable of oxidatively metabolizing the carbon skeleton of BCAAs, particularly to support glutamine synthesis. Interestingly, hiPSC-derived astrocytes with APP and PSEN-1 mutations exhibited decreased amino acid synthesis of glutamate, glutamine, and aspartate derived from leucine metabolism. These results clearly demonstrate that there is an active BCAA metabolism in human astrocytes, and that leucine metabolism is selectively impaired in astrocytes derived from the hiPSC models of AD. This impairment in astrocytic BCAA metabolism may contribute to neurotransmitter and energetic imbalances in the AD brain.

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“…We have previously shown that BCATc is phosphorylated through redox-regulated PKC activation [16]. The BCAT proteins also have various phosphorylation motifs for MAPK defined using the Motif Scan program (http://scansite.mit.edu) (Figure 6A), highlighting 3 structurally accessible consensus sequences for MAPK, T33, S188 and T278 (Figure 6B).…”

Section: Bcatc Significantly Reduces Igf-1 Mediated Activation Of Erkmentioning

confidence: 95%

“…Emerging evidence has indicated that the BCAT proteins, traditionally assigned metabolic roles, may have additional 'moonlighting' cellular functions, which are regulated through their peroxide sensitive-redox active CXXC motif [15]. We have recently established that the BCAT proteins can form thiol-dependent interactions with key signalling molecules such as those in the PI3K/Akt and the Ras/ERK pathways (unpublished observations) and show that phosphorylation of BCAT by PKC kinases is redox-dependent [16]. We showed that BCATc regulated autophagy through an interdependence of redox-regulated phosphorylation, supporting a 'moonlighting' role for this metabolic protein.…”

Section: Research Papermentioning

confidence: 99%

“…Under normal cellular conditions, the metabolite α-ketoglutarate, the product of leucine transamination, activates mTOR. However, BCAT is regulated through phosphorylation and changes in the redox environment, which can prompt BCATc to associate with other signalling pathways, dependent on the stimuli, such as nutrient load, insulin/IGF-1 or changes in the redox environment [16]. Therefore, in response to IGF-1 or insulin the role of BCATc may switch from supporting mTOR activation to associate with proteins from the PI3K/Akt pathway.…”

Section: Bcatc Regulates Cross-talk Between the Ras/ Erk And Pi3k/akt Pathwaysmentioning

confidence: 99%

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BCATc modulates crosstalk between the PI3K/Akt and the Ras/ERK pathway regulating proliferation in triple negative breast cancer

et al. 2020

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The cytosolic branched chain aminotransferase (BCATc) protein has been found to be highly expressed in breast cancer subtypes, including triple negative breast cancer (TNBC), compared with normal breast tissue. The catabolism of branched-chain amino acids (BCAAs) by BCATc leads to the production of glutamate and key metabolites which further drive the TCA cycle, important for cellular metabolism and growth. Upregulation of BCATc has been associated with increased cell proliferation, cell cycle progression and metastasis in several malignancies including breast, gliomas, ovarian and colorectal cancer but the underlying mechanisms are unclear. As nutrient levels of BCAAs, substrates of BCATc, regulate the PI3K/Akt pathway we hypothesized that increased expression of BCATc would contribute to tumour cell growth through upregulation of the insulin/IGF-1 signalling pathway. This pathway is known to potentiate proliferation and metastasis of malignant cells through the activation of PI3K/Akt and the RAS/ERK signalling cascades. Here we show that knockdown of BCATc significantly reduced insulin and IGF-1-mediated proliferation, migration and invasion of TNBC cells. An analysis of this pathway showed that when overexpressed BCATc regulates proliferation through the PI3K/Akt axis, whilst simultaneously attenuating the Ras/Erk pathway indicating that BCATc acts as a conduit between these two pathways. This ultimately led to an increase in FOXO3a, a key regulator of cell proliferation and Nrf2, which mediates redox homeostasis. Together this data indicates that BCATc regulates TNBC cell proliferation, migration and invasion through the IGF-1/insulin PI3K/Akt pathway, culminating in the upregulation of FOXO3a and Nrf2, pointing to a novel therapeutic target for breast cancer treatment.

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BCAT-induced autophagy regulates Aβ load through an interdependence of redox state and PKC phosphorylation-implications in Alzheimer's disease

Cited by 15 publications

References 72 publications

Alzheimer’s disease: targeting the glutamatergic system

Alzheimer’s disease: targeting the glutamatergic system

Functional Metabolic Mapping Reveals Highly Active Branched-Chain Amino Acid Metabolism in Human Astrocytes, Which Is Impaired in iPSC-Derived Astrocytes in Alzheimer's Disease

BCATc modulates crosstalk between the PI3K/Akt and the Ras/ERK pathway regulating proliferation in triple negative breast cancer

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