Publications by authors named "Peter L Oliver"

72 Publications

Zfhx3-mediated genetic ablation of the SCN abolishes light entrainable circadian activity while sparing food anticipatory activity.

iScience 2021 Oct 16;24(10):103142. Epub 2021 Sep 16.

MRC Harwell Institute, Harwell Science Campus, Oxfordshire OX11 0RD, UK.

Circadian rhythms persist in almost all organisms and are crucial for maintaining appropriate timing in physiology and behaviour. Here, we describe a mouse mutant where the central mammalian pacemaker, the suprachiasmatic nucleus (SCN), has been genetically ablated by conditional deletion of the transcription factor in the developing hypothalamus. Mutants were arrhythmic over the light-dark cycle and in constant darkness. Moreover, rhythms of metabolic parameters were ablated although molecular oscillations in the liver maintained some rhythmicity. Despite disruptions to SCN cell identity and circuitry, mutants could still anticipate food availability, yet other zeitgebers - including social cues from cage-mates - were ineffective in restoring rhythmicity although activity levels in mutants were altered. This work highlights a critical role for in the development of a functional SCN, while its genetic ablation further defines the contribution of SCN circuitry in orchestrating physiological and behavioral responses to environmental signals.
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http://dx.doi.org/10.1016/j.isci.2021.103142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487057PMC
October 2021

Behavioural Characterisation of and Knockout Mice.

Cells 2021 02 10;10(2). Epub 2021 Feb 10.

Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.

Adenosine diphosphate ribosylation (ADP-ribosylation; ADPr), the addition of ADP-ribose moieties onto proteins and nucleic acids, is a highly conserved modification involved in a wide range of cellular functions, from viral defence, DNA damage response (DDR), metabolism, carcinogenesis and neurobiology. Here we study MACROD1 and MACROD2 (mono-ADP-ribosylhydrolases 1 and 2), two of the least well-understood ADPr-mono-hydrolases. MACROD1 has been reported to be largely localized to the mitochondria, while the genomic locus has been associated with various neurological conditions such as autism, attention deficit hyperactivity disorder (ADHD) and schizophrenia; yet the potential significance of disrupting these proteins in the context of mammalian behaviour is unknown. Therefore, here we analysed both and gene knockout (KO) mouse models in a battery of well-defined, spontaneous behavioural testing paradigms. Loss of resulted in a female-specific motor-coordination defect, whereas disruption was associated with hyperactivity that became more pronounced with age, in combination with a bradykinesia-like gait. These data reveal new insights into the importance of ADPr-mono-hydrolases in aspects of behaviour associated with both mitochondrial and neuropsychiatric disorders.
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http://dx.doi.org/10.3390/cells10020368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916507PMC
February 2021

Gv1, a Zinc Finger Gene Controlling Endogenous MLV Expression.

Mol Biol Evol 2021 05;38(6):2468-2474

Retrovirus-host Interactions Laboratory, The Francis Crick Institute, London, UK.

The genomes of inbred mice harbor around 50 endogenous murine leukemia virus (MLV) loci, although the specific complement varies greatly between strains. The Gv1 locus is known to control the transcription of endogenous MLVs and to be the dominant determinant of cell-surface presentation of MLV envelope, the GIX antigen. Here, we identify a single Krüppel-associated box zinc finger protein (ZFP) gene, Zfp998, as Gv1 and show it to be necessary and sufficient to determine the GIX+ phenotype. By long-read sequencing of bacterial artificial chromosome clones from 129 mice, the prototypic GIX+ strain, we reveal the source of sufficiency and deficiency as splice-acceptor variations and highlight the varying origins of the chromosomal region encompassing Gv1. Zfp998 becomes the second identified ZFP gene responsible for epigenetic suppression of endogenous MLVs in mice and further highlights the prominent role of this gene family in control of endogenous retroviruses.
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http://dx.doi.org/10.1093/molbev/msab039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136514PMC
May 2021

The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour.

Cell Mol Life Sci 2021 Apr 19;78(7):3503-3524. Epub 2020 Dec 19.

MRC Harwell Institute, Harwell Campus, Oxfordshire, OX11 0RD, UK.

Members of the Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) protein family are associated with multiple neurodevelopmental disorders, although their exact roles in disease remain unclear. For example, nuclear receptor coactivator 7 (NCOA7) has been associated with autism, although almost nothing is known regarding the mode-of-action of this TLDc protein in the nervous system. Here we investigated the molecular function of NCOA7 in neurons and generated a novel mouse model to determine the consequences of deleting this locus in vivo. We show that NCOA7 interacts with the cytoplasmic domain of the vacuolar (V)-ATPase in the brain and demonstrate that this protein is required for normal assembly and activity of this critical proton pump. Neurons lacking Ncoa7 exhibit altered development alongside defective lysosomal formation and function; accordingly, Ncoa7 deletion animals exhibited abnormal neuronal patterning defects and a reduced expression of lysosomal markers. Furthermore, behavioural assessment revealed anxiety and social defects in mice lacking Ncoa7. In summary, we demonstrate that NCOA7 is an important V-ATPase regulatory protein in the brain, modulating lysosomal function, neuronal connectivity and behaviour; thus our study reveals a molecular mechanism controlling endolysosomal homeostasis that is essential for neurodevelopment.
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http://dx.doi.org/10.1007/s00018-020-03721-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038996PMC
April 2021

ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease.

Antioxidants (Basel) 2020 Aug 13;9(8). Epub 2020 Aug 13.

Mammalian Genetics Unit, MRC Harwell Institute, Harwell, Oxfordshire OX11 0RD, UK.

Neurodegenerative disorders, such as Alzheimer's disease, are a global public health burden with poorly understood aetiology. Neuroinflammation and oxidative stress (OS) are undoubtedly hallmarks of neurodegeneration, contributing to disease progression. Protein aggregation and neuronal damage result in the activation of disease-associated microglia (DAM) via damage-associated molecular patterns (DAMPs). DAM facilitate persistent inflammation and reactive oxygen species (ROS) generation. However, the molecular mechanisms linking DAM activation and OS have not been well-defined; thus targeting these cells for clinical benefit has not been possible. In microglia, ROS are generated primarily by NADPH oxidase 2 (NOX2) and activation of NOX2 in DAM is associated with DAMP signalling, inflammation and amyloid plaque deposition, especially in the cerebrovasculature. Additionally, ROS originating from both NOX and the mitochondria may act as second messengers to propagate immune activation; thus intracellular ROS signalling may underlie excessive inflammation and OS. Targeting key kinases in the inflammatory response could cease inflammation and promote tissue repair. Expression of antioxidant proteins in microglia, such as NADPH dehydrogenase 1 (NQO1), is promoted by transcription factor Nrf2, which functions to control inflammation and limit OS. Lipid droplet accumulating microglia (LDAM) may also represent a double-edged sword in neurodegenerative disease by sequestering peroxidised lipids in non-pathological ageing but becoming dysregulated and pro-inflammatory in disease. We suggest that future studies should focus on targeted manipulation of NOX in the microglia to understand the molecular mechanisms driving inflammatory-related NOX activation. Finally, we discuss recent evidence that therapeutic target identification should be unbiased and founded on relevant pathophysiological assays to facilitate the discovery of translatable antioxidant and anti-inflammatory therapeutics.
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http://dx.doi.org/10.3390/antiox9080743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463655PMC
August 2020

Impairment of Macroautophagy in Dopamine Neurons Has Opposing Effects on Parkinsonian Pathology and Behavior.

Cell Rep 2019 10;29(4):920-931.e7

Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK. Electronic address:

Parkinson's disease (PD) is characterized by the death of dopamine neurons in the substantia nigra pars compacta (SNc) and accumulation of α-synuclein. Impaired autophagy has been implicated and activation of autophagy proposed as a treatment strategy. We generate a human α-synuclein-expressing mouse model of PD with macroautophagic failure in dopamine neurons to understand the interaction between impaired macroautophagy and α-synuclein. We find that impaired macroautophagy generates p62-positive inclusions and progressive neuron loss in the SNc. Despite this parkinsonian pathology, motor phenotypes accompanying human α-synuclein overexpression actually improve with impaired macroautophagy. Real-time fast-scan cyclic voltammetry reveals that macroautophagy impairment in dopamine neurons increases evoked extracellular concentrations of dopamine, reduces dopamine uptake, and relieves paired-stimulus depression. Our findings show that impaired macroautophagy paradoxically enhances dopamine neurotransmission, improving movement while worsening pathology, suggesting that changes to dopamine synapse function compensate for and conceal the underlying PD pathogenesis, with implications for therapies that target autophagy.
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http://dx.doi.org/10.1016/j.celrep.2019.09.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856726PMC
October 2019

Neuronal over-expression of Oxr1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo.

Hum Mol Genet 2019 11;28(21):3584-3599

Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.

A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and the related neurodegenerative disorder frontotemporal dementia, is the cellular mislocalization of transactive response DNA-binding protein 43 kDa (TDP-43). Additionally, multiple mutations in the TARDBP gene (encoding TDP-43) are associated with familial forms of ALS. While the exact role for TDP-43 in the onset and progression of ALS remains unclear, the identification of factors that can prevent aberrant TDP-43 localization and function could be clinically beneficial. Previously, we discovered that the oxidation resistance 1 (Oxr1) protein could alleviate cellular mislocalization phenotypes associated with TDP-43 mutations, and that over-expression of Oxr1 was able to delay neuromuscular abnormalities in the hSOD1G93A ALS mouse model. Here, to determine whether Oxr1 can protect against TDP-43-associated phenotypes in vitro and in vivo, we used the same genetic approach in a newly described transgenic mouse expressing the human TDP-43 locus harbouring an ALS disease mutation (TDP-43M337V). We show in primary motor neurons from TDP-43M337V mice that genetically-driven Oxr1 over-expression significantly alleviates cytoplasmic mislocalization of mutant TDP-43. We also further quantified newly-identified, late-onset neuromuscular phenotypes of this mutant line, and demonstrate that neuronal Oxr1 over-expression causes a significant reduction in muscle denervation and neuromuscular junction degeneration in homozygous mutants in parallel with improved motor function and a reduction in neuroinflammation. Together these data support the application of Oxr1 as a viable and safe modifier of TDP-43-associated ALS phenotypes.
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http://dx.doi.org/10.1093/hmg/ddz190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927465PMC
November 2019

Limitations to adaptive homeostasis in an hyperoxia-induced model of accelerated ageing.

Redox Biol 2019 06 14;24:101194. Epub 2019 Apr 14.

Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, University of Southern California, Los Angeles, CA 90089-0191, USA; Division of Molecular & Computational Biology, Department of Biological Sciences of the Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA 90089-0191, USA; Department of Biochemistry & Molecular Medicine, Keck School of Medicine of USC, University of Southern California, University of Southern California, Los Angeles, CA 90089-0191, USA. Electronic address:

The Nrf2 signal transduction pathway plays a major role in adaptive responses to oxidative stress and in maintaining adaptive homeostasis, yet Nrf2 signaling undergoes a significant age-dependent decline that is still poorly understood. We used mouse embryonic fibroblasts (MEFs) cultured under hyperoxic conditions of 40% O, as a model of accelerated ageing. Hyperoxia increased baseline levels of Nrf2 and multiple transcriptional targets (20S Proteasome, Immunoproteasome, Lon protease, NQO1, and HO-1), but resulted in loss of cellular ability to adapt to signaling levels (1.0 μM) of HO. In contrast, MEFs cultured at physiologically relevant conditions of 5% O exhibited a transient induction of Nrf2 Phase II target genes and stress-protective enzymes (the Lon protease and OXR1) following HO treatment. Importantly, all of these effects have been seen in older cells and organisms. Levels of Two major Nrf2 inhibitors, Bach1 and c-Myc, were strongly elevated by hyperoxia and appeared to exert a ceiling on Nrf2 signaling. Bach1 and c-Myc also increase during ageing and may thus be the mechanism by which adaptive homeostasis is compromised with age.
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http://dx.doi.org/10.1016/j.redox.2019.101194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479762PMC
June 2019

Loss of disrupts synaptic AMPA receptor function, and results in neurodevelopmental, motor, cognitive and electrographical abnormalities.

Dis Model Mech 2019 02 22;12(2). Epub 2019 Feb 22.

MRC Harwell Institute, Harwell Campus, Oxfordshire OX11 0RD, UK

Loss-of-function mutations in a human AMPA receptor-associated protein, ferric chelate reductase 1-like (FRRS1L), are associated with a devastating neurological condition incorporating choreoathetosis, cognitive deficits and epileptic encephalopathies. Furthermore, evidence from overexpression and studies has implicated FRRS1L in AMPA receptor biogenesis, suggesting that changes in glutamatergic signalling might underlie the disorder. Here, we investigated the neurological and neurobehavioural correlates of the disorder using a mouse null mutant. The study revealed several neurological defects that mirrored those seen in human patients. We established that mice lacking suffered from a broad spectrum of early-onset motor deficits with no progressive, age-related deterioration. Moreover, mice were hyperactive, irrespective of test environment, exhibited working memory deficits and displayed significant sleep fragmentation. Longitudinal electroencephalographic (EEG) recordings also revealed abnormal EEG results in mice. Parallel investigations into disease aetiology identified a specific deficiency in AMPA receptor levels in the brain of mice, while the general levels of several other synaptic components remained unchanged, with no obvious alterations in the number of synapses. Furthermore, we established that deletion results in an increased proportion of immature AMPA receptors, indicated by incomplete glycosylation of GLUA2 (also known as GRIA2) and GLUA4 (also known as GRIA4) AMPA receptor proteins. This incomplete maturation leads to cytoplasmic retention and a reduction of those specific AMPA receptor levels in the postsynaptic membrane. Overall, this study determines, for the first time , how loss of FRRS1L function can affect glutamatergic signalling, and provides mechanistic insight into the development and progression of a human hyperkinetic disorder.This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/dmm.036806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398485PMC
February 2019

Oxidation resistance 1 regulates post-translational modifications of peroxiredoxin 2 in the cerebellum.

Free Radic Biol Med 2019 01 31;130:151-162. Epub 2018 Oct 31.

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK. Electronic address:

Protein aggregation, oxidative and nitrosative stress are etiological factors common to all major neurodegenerative disorders. Therefore, identifying proteins that function at the crossroads of these essential pathways may provide novel targets for therapy. Oxidation resistance 1 (Oxr1) is a protein proven to be neuroprotective against oxidative stress, although the molecular mechanisms involved remain unclear. Here, we demonstrate that Oxr1 interacts with the multifunctional protein, peroxiredoxin 2 (Prdx2), a potent antioxidant enzyme highly expressed in the brain that can also act as a molecular chaperone. Using a combination of in vitro assays and two animal models, we discovered that expression levels of Oxr1 regulate the degree of oligomerization of Prdx2 and also its post-translational modifications (PTMs), specifically suggesting that Oxr1 acts as a functional switch between the antioxidant and chaperone functions of Prdx2. Furthermore, we showed in the Oxr1 knockout mouse that Prdx2 is aberrantly modified by overoxidation and S-nitrosylation in the cerebellum at the presymptomatic stage; this in-turn affected the oligomerization of Prdx2, potentially impeding its normal functions and contributing to the specific cerebellar neurodegeneration in this mouse model.
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http://dx.doi.org/10.1016/j.freeradbiomed.2018.10.447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339520PMC
January 2019

The epilepsy-associated protein TBC1D24 is required for normal development, survival and vesicle trafficking in mammalian neurons.

Hum Mol Genet 2019 02;28(4):584-597

Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, UK.

Mutations in the Tre2/Bub2/Cdc16 (TBC)1 domain family member 24 (TBC1D24) gene are associated with a range of inherited neurological disorders, from drug-refractory lethal epileptic encephalopathy and DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures) to non-syndromic hearing loss. TBC1D24 has been implicated in neuronal transmission and maturation, although the molecular function of the gene and the cause of the apparently complex disease spectrum remain unclear. Importantly, heterozygous TBC1D24 mutation carriers have also been reported with seizures, suggesting that haploinsufficiency for TBC1D24 is significant clinically. Here we have systematically investigated an allelic series of disease-associated mutations in neurons alongside a new mouse model to investigate the consequences of TBC1D24 haploinsufficiency to mammalian neurodevelopment and synaptic physiology. The cellular studies reveal that disease-causing mutations that disrupt either of the conserved protein domains in TBC1D24 are implicated in neuronal development and survival and are likely acting as loss-of-function alleles. We then further investigated TBC1D24 haploinsufficiency in vivo and demonstrate that TBC1D24 is also crucial for normal presynaptic function: genetic disruption of Tbc1d24 expression in the mouse leads to an impairment of endocytosis and an enlarged endosomal compartment in neurons with a decrease in spontaneous neurotransmission. These data reveal the essential role for TBC1D24 at the mammalian synapse and help to define common synaptic mechanisms that could underlie the varied effects of TBC1D24 mutations in neurological disease.
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http://dx.doi.org/10.1093/hmg/ddy370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360273PMC
February 2019

Single-copy expression of an amyotrophic lateral sclerosis-linked TDP-43 mutation (M337V) in BAC transgenic mice leads to altered stress granule dynamics and progressive motor dysfunction.

Neurobiol Dis 2019 01 2;121:148-162. Epub 2018 Oct 2.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. Electronic address:

Mutations in the gene encoding the RNA-binding protein TDP-43 cause amyotrophic lateral sclerosis (ALS), clinically and pathologically indistinguishable from the majority of 'sporadic' cases of ALS, establishing altered TDP-43 function and distribution as a primary mechanism of neurodegeneration. Transgenic mouse models in which TDP-43 is overexpressed only partially recapitulate the key cellular pathology of human ALS, but may also lead to non-specific toxicity. To avoid the potentially confounding effects of overexpression, and to maintain regulated spatio-temporal and cell-specific expression, we generated mice in which an 80 kb genomic fragment containing the intact human TDP-43 locus (either TDP-43 or TDP-43) and its regulatory regions was integrated into the Rosa26 (Gt(ROSA26)Sor) locus in a single copy. At 3 months of age, TDP-43 mice are phenotypically normal but by around 6 months develop progressive motor function deficits associated with loss of neuromuscular junction integrity, leading to a reduced lifespan. RNA sequencing shows that widespread mis-splicing is absent prior to the development of a motor phenotype, though differential expression analysis reveals a distinct transcriptional profile in pre-symptomatic TDP-43 spinal cords. Despite the presence of clear motor abnormalities, there was no evidence of TDP-43 cytoplasmic aggregation in vivo at any timepoint. In primary embryonic spinal motor neurons and in embryonic stem cell (ESC)-derived motor neurons, mutant TDP-43 undergoes cytoplasmic mislocalisation, and is associated with altered stress granule assembly and dynamics. Overall, this mouse model provides evidence that ALS may arise through acquired TDP-43 toxicity associated with defective stress granule function. The normal phenotype until 6 months of age can facilitate the study of early pathways underlying ALS.
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http://dx.doi.org/10.1016/j.nbd.2018.09.024DOI Listing
January 2019

Absent sleep EEG spindle activity in GluA1 (Gria1) knockout mice: relevance to neuropsychiatric disorders.

Transl Psychiatry 2018 08 14;8(1):154. Epub 2018 Aug 14.

Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.

Sleep EEG spindles have been implicated in attention, sensory processing, synaptic plasticity and memory consolidation. In humans, deficits in sleep spindles have been reported in a wide range of neurological and psychiatric disorders, including schizophrenia. Genome-wide association studies have suggested a link between schizophrenia and genes associated with synaptic plasticity, including the Gria1 gene which codes for the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. Gria1 mice exhibit a phenotype relevant for neuropsychiatric disorders, including reduced synaptic plasticity and, at the behavioural level, attentional deficits leading to aberrant salience. In this study we report a striking reduction of EEG power density including the spindle-frequency range (10-15 Hz) during sleep in Gria1 mice. The reduction of spindle-activity in Gria1 mice was accompanied by longer REM sleep episodes, increased EEG slow-wave activity in the occipital derivation during baseline sleep, and a reduced rate of decline of EEG slow wave activity (0.5-4 Hz) during NREM sleep after sleep deprivation. These data provide a novel link between glutamatergic dysfunction and sleep abnormalities in a schizophrenia-relevant mouse model.
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http://dx.doi.org/10.1038/s41398-018-0199-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092338PMC
August 2018

Oxidation Resistance 1 Modulates Glycolytic Pathways in the Cerebellum via an Interaction with Glucose-6-Phosphate Isomerase.

Mol Neurobiol 2019 Mar 15;56(3):1558-1577. Epub 2018 Jun 15.

Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.

Glucose metabolism is essential for the brain: it not only provides the required energy for cellular function and communication but also participates in balancing the levels of oxidative stress in neurons. Defects in glucose metabolism have been described in neurodegenerative disease; however, it remains unclear how this fundamental process contributes to neuronal cell death in these disorders. Here, we investigated the molecular mechanisms driving the selective neurodegeneration in an ataxic mouse model lacking oxidation resistance 1 (Oxr1) and discovered an unexpected function for this protein as a regulator of the glycolytic enzyme, glucose-6-phosphate isomerase (GPI/Gpi1). Initially, we present a dysregulation of metabolites of glucose metabolism at the pre-symptomatic stage in the Oxr1 knockout cerebellum. We then demonstrate that Oxr1 and Gpi1 physically and functionally interact and that the level of Gpi1 oligomerisation is disrupted when Oxr1 is deleted in vivo. Furthermore, we show that Oxr1 modulates the additional and less well-understood roles of Gpi1 as a cytokine and neuroprotective factor. Overall, our data identify a new molecular function for Oxr1, establishing this protein as important player in neuronal survival, regulating both oxidative stress and glucose metabolism in the brain.
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http://dx.doi.org/10.1007/s12035-018-1174-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368252PMC
March 2019

Targeted deletion of the Ncoa7 gene results in incomplete distal renal tubular acidosis in mice.

Am J Physiol Renal Physiol 2018 07 31;315(1):F173-F185. Epub 2018 Jan 31.

Center for Systems Biology, Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital and Harvard Medical School , Boston, Massachusetts.

We recently reported that nuclear receptor coactivator 7 (Ncoa7) is a vacuolar proton pumping ATPase (V-ATPase) interacting protein whose function has not been defined. Ncoa7 is highly expressed in the kidney and partially colocalizes with the V-ATPase in collecting duct intercalated cells (ICs). Here, we hypothesized that targeted deletion of the Ncoa7 gene could affect V-ATPase activity in ICs in vivo. We tested this by analyzing the acid-base status, major electrolytes, and kidney morphology of Ncoa7 knockout (KO) mice. We found that Ncoa7 KO mice, similar to Atp6v1b1 KOs, did not develop severe distal renal tubular acidosis (dRTA), but they exhibited a persistently high urine pH and developed hypobicarbonatemia after acid loading with ammonium chloride. Conversely, they did not develop significant hyperbicarbonatemia and alkalemia after alkali loading with sodium bicarbonate. We also found that ICs were larger and with more developed apical microvilli in Ncoa7 KO compared with wild-type mice, a phenotype previously associated with metabolic acidosis. At the molecular level, the abundance of several V-ATPase subunits, carbonic anhydrase 2, and the anion exchanger 1 was significantly reduced in medullary ICs of Ncoa7 KO mice, suggesting that Ncoa7 is important for maintaining high levels of these proteins in the kidney. We conclude that Ncoa7 is involved in IC function and urine acidification in mice in vivo, likely through modulating the abundance of V-ATPase and other key acid-base regulators in the renal medulla. Consequently, mutations in the NCOA7 gene may also be involved in dRTA pathogenesis in humans.
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http://dx.doi.org/10.1152/ajprenal.00407.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087784PMC
July 2018

TLDc proteins: new players in the oxidative stress response and neurological disease.

Mamm Genome 2017 10 13;28(9-10):395-406. Epub 2017 Jul 13.

Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.

Oxidative stress (OS) arises from an imbalance in the cellular redox state, which can lead to intracellular damage and ultimately cell death. OS occurs as a result of normal ageing, but it is also implicated as a common etiological factor in neurological disease; thus identifying novel proteins that modulate the OS response may facilitate the design of new therapeutic approaches applicable to many disorders. In this review, we describe the recent progress that has been made using a range of genetic approaches to understand a family of proteins that share the highly conserved TLDc domain. We highlight their shared ability to prevent OS-related cell death and their unique functional characteristics, as well as discussing their potential application as new neuroprotective factors. Furthermore, with an increasing number of pathogenic mutations leading to epilepsy and hearing loss being discovered in the TLDc protein TBC1D24, understanding the function of this family has important implications for a range of inherited neurological diseases.
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http://dx.doi.org/10.1007/s00335-017-9706-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614904PMC
October 2017

Wild-Type, but Not Mutant N296H, Human Tau Restores Aβ-Mediated Inhibition of LTP in mice.

Front Neurosci 2017 24;11:201. Epub 2017 Apr 24.

Department of Physiology, Anatomy and Genetics, University of OxfordOxford, UK.

Microtubule associated protein tau (MAPT) is involved in the pathogenesis of Alzheimer's disease and many forms of frontotemporal dementia (FTD). We recently reported that Aβ-mediated inhibition of hippocampal long-term potentiation (LTP) in mice requires tau. Here, we asked whether expression of human can restore Aβ-mediated inhibition on a mouse background and whether human tau with an FTD-causing mutation (N296H) can interfere with Aβ-mediated inhibition of LTP. We used transgenic mouse lines each expressing the full human locus using bacterial artificial chromosome technology. These lines expressed all six human tau protein isoforms on a background. We found that the human wild-type H1 locus was able to restore Aβ-mediated impairment of LTP. In contrast, Aβ did not reduce LTP in slices in two independently generated transgenic lines expressing tau protein with the mutation N296H associated with frontotemporal dementia (FTD). Basal phosphorylation of tau measured as the ratio of AT8/Tau5 immunoreactivity was significantly reduced in N296H mutant hippocampal slices. Our data show that human is able to restore Aβ-mediated inhibition of LTP in mice. These results provide further evidence that tau protein is central to Aβ-induced LTP impairment and provide a valuable tool for further analysis of the links between Aβ, human tau and impairment of synaptic function.
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http://dx.doi.org/10.3389/fnins.2017.00201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5401872PMC
April 2017

Increased 4R tau expression and behavioural changes in a novel MAPT-N296H genomic mouse model of tauopathy.

Sci Rep 2017 02 24;7:43198. Epub 2017 Feb 24.

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.

The microtubule-associated protein tau is implicated in various neurodegenerative diseases including Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration, which are characterized by intracellular accumulation of hyperphosphorylated tau. Mutations in the tau gene MAPT cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). In the human central nervous system, six tau isoforms are expressed, and imbalances in tau isoform ratios are associated with pathology. To date, few animal models of tauopathy allow for the potential influence of these protein isoforms, relying instead on cDNA-based transgene expression. Using the P1-derived artificial chromosome (PAC) technology, we created mouse lines expressing all six tau isoforms from the human MAPT locus, harbouring either the wild-type sequence or the disease-associated N296H mutation on an endogenous Mapt-/- background. Animals expressing N296H mutant tau recapitulated early key features of tauopathic disease, including a tau isoform imbalance and tau hyperphosphorylation in the absence of somatodendritic tau inclusions. Furthermore, N296H animals displayed behavioural anomalies such as hyperactivity, increased time in the open arms of the elevated plus maze and increased immobility during the tail suspension test. The mouse models described provide an excellent model to study the function of wild-type or mutant tau in a highly physiological setting.
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http://dx.doi.org/10.1038/srep43198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324134PMC
February 2017

Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation.

Hum Mol Genet 2017 03;26(5):873-887

Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.

Frontotemporal dementia (FTD)-causing mutations in the CHMP2B gene lead to the generation of mutant C-terminally truncated CHMP2B. We report that transgenic mice expressing endogenous levels of mutant CHMP2B developed late-onset brain volume loss associated with frank neuronal loss and FTD-like changes in social behaviour. These data are the first to show neurodegeneration in mice expressing mutant CHMP2B and indicate that our mouse model is able to recapitulate neurodegenerative changes observed in FTD. Neuroinflammation has been increasingly implicated in neurodegeneration, including FTD. Therefore, we investigated neuroinflammation in our CHMP2B mutant mice. We observed very early microglial proliferation that develops into a clear pro-inflammatory phenotype at late stages. Importantly, we also observed a similar inflammatory profile in CHMP2B patient frontal cortex. Aberrant microglial function has also been implicated in FTD caused by GRN, MAPT and C9orf72 mutations. The presence of early microglial changes in our CHMP2B mutant mice indicates neuroinflammation may be a contributing factor to the neurodegeneration observed in FTD.
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http://dx.doi.org/10.1093/hmg/ddx003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409096PMC
March 2017

Stereotypic wheel running decreases cortical activity in mice.

Nat Commun 2016 10 17;7:13138. Epub 2016 Oct 17.

Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.

Prolonged wakefulness is thought to gradually increase 'sleep need' and influence subsequent sleep duration and intensity, but the role of specific waking behaviours remains unclear. Here we report the effect of voluntary wheel running during wakefulness on neuronal activity in the motor and somatosensory cortex in mice. We find that stereotypic wheel running is associated with a substantial reduction in firing rates among a large subpopulation of cortical neurons, especially at high speeds. Wheel running also has longer-term effects on spiking activity across periods of wakefulness. Specifically, cortical firing rates are significantly higher towards the end of a spontaneous prolonged waking period. However, this increase is abolished when wakefulness is dominated by running wheel activity. These findings indicate that wake-related changes in firing rates are determined not only by wake duration, but also by specific waking behaviours.
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http://dx.doi.org/10.1038/ncomms13138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5071642PMC
October 2016

TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features.

Neurology 2016 07 8;87(1):77-85. Epub 2016 Jun 8.

Objective: To evaluate the phenotypic spectrum associated with mutations in TBC1D24.

Methods: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24).

Results: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function.

Conclusions: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.
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http://dx.doi.org/10.1212/WNL.0000000000002807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4932231PMC
July 2016

Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function.

Cell Metab 2016 May 28;23(5):821-36. Epub 2016 Apr 28.

Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease.
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http://dx.doi.org/10.1016/j.cmet.2016.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873618PMC
May 2016

The antioxidant protein Oxr1 influences aspects of mitochondrial morphology.

Free Radic Biol Med 2016 06 29;95:255-67. Epub 2016 Mar 29.

MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK. Electronic address:

Oxidative stress (OS) and mitochondrial dysfunction are implicated in neurodegenerative disease, suggesting that antioxidant defence systems are critical for cell survival in the central nervous system (CNS). Oxidation resistance 1 (OXR1) can protect against OS in cellular and mouse models of amyotrophic lateral sclerosis (ALS) when over-expressed, whereas deletion of Oxr1 in mice causes neurodegeneration. OXR1 has emerged therefore as an essential antioxidant protein that controls the susceptibility of neurons to OS. It has been suggested that OXR1 is localised to mitochondria, yet the functional significance of this has not been investigated in the context of neuronal cell death. In order to characterise the role of Oxr1 in mitochondria, we investigated its sub-mitochondrial localisation and demonstrate that specific isoforms are associated with the outer mitochondrial membrane, while the full-length Oxr1 protein is predominately cytoplasmic. Interestingly, cytoplamsic over-expression of these mitochondrially-localised isoforms was still able to protect against OS-induced cell death and prevent rotenone-induced mitochondrial morphological changes. To study the consequences of Oxr1 deletion in vivo, we utilised the bella ataxic mouse mutant. We were unable to identify defects in mitochondrial metabolism in primary cerebellar granule cells (GCs) from bella mice, however a reduction in mitochondrial length was observed in mutant GCs compared to those from wild-type. Furthermore, screening a panel of proteins that regulate mitochondrial morphology in bella GCs revealed de-regulation of phospho-Drp1(Ser616), a key mitochondrial fission regulatory factor. Our data provide new insights into the function of Oxr1, revealing that specific isoforms of this novel antioxidant protein are associated with mitochondria and that the modulation of mitochondrial morphology may be an important feature of its protective function. These results have important implications for the potential use of OXR1 in future antioxidant therapies.
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http://dx.doi.org/10.1016/j.freeradbiomed.2016.03.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891067PMC
June 2016

The Evolutionarily Conserved Tre2/Bub2/Cdc16 (TBC), Lysin Motif (LysM), Domain Catalytic (TLDc) Domain Is Neuroprotective against Oxidative Stress.

J Biol Chem 2016 Feb 14;291(6):2751-63. Epub 2015 Dec 14.

From the MRC Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom

Oxidative stress is a pathological feature of many neurological disorders; therefore, utilizing proteins that are protective against such cellular insults is a potentially valuable therapeutic approach. Oxidation resistance 1 (OXR1) has been shown previously to be critical for oxidative stress resistance in neuronal cells; deletion of this gene causes neurodegeneration in mice, yet conversely, overexpression of OXR1 is protective in cellular and mouse models of amyotrophic lateral sclerosis. However, the molecular mechanisms involved are unclear. OXR1 contains the Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) domain, a motif present in a family of proteins including TBC1 domain family member 24 (TBC1D24), a protein mutated in a range of disorders characterized by seizures, hearing loss, and neurodegeneration. The TLDc domain is highly conserved across species, although the structure-function relationship is unknown. To understand the role of this domain in the stress response, we carried out systematic analysis of all mammalian TLDc domain-containing proteins, investigating their expression and neuroprotective properties in parallel. In addition, we performed a detailed structural and functional study of this domain in which we identified key residues required for its activity. Finally, we present a new mouse insertional mutant of Oxr1, confirming that specific disruption of the TLDc domain in vivo is sufficient to cause neurodegeneration. Our data demonstrate that the integrity of the TLDc domain is essential for conferring neuroprotection, an important step in understanding the functional significance of all TLDc domain-containing proteins in the cellular stress response and disease.
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http://dx.doi.org/10.1074/jbc.M115.685222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742741PMC
February 2016

Temporal transcriptomics suggest that twin-peaking genes reset the clock.

Elife 2015 Nov 2;4. Epub 2015 Nov 2.

MRC Functional Genomics Unit, Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.

The mammalian suprachiasmatic nucleus (SCN) drives daily rhythmic behavior and physiology, yet a detailed understanding of its coordinated transcriptional programmes is lacking. To reveal the finer details of circadian variation in the mammalian SCN transcriptome we combined laser-capture microdissection (LCM) and RNA-seq over a 24 hr light / dark cycle. We show that 7-times more genes exhibited a classic sinusoidal expression signature than previously observed in the SCN. Another group of 766 genes unexpectedly peaked twice, near both the start and end of the dark phase; this twin-peaking group is significantly enriched for synaptic transmission genes that are crucial for light-induced phase shifting of the circadian clock. 341 intergenic non-coding RNAs, together with novel exons of annotated protein-coding genes, including Cry1, also show specific circadian expression variation. Overall, our data provide an important chronobiological resource (www.wgpembroke.com/shiny/SCNseq/) and allow us to propose that transcriptional timing in the SCN is gating clock resetting mechanisms.
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http://dx.doi.org/10.7554/eLife.10518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718813PMC
November 2015

Circadian profiling in two mouse models of lysosomal storage disorders; Niemann Pick type-C and Sandhoff disease.

Behav Brain Res 2016 Jan 20;297:213-23. Epub 2015 Oct 20.

Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK. Electronic address:

Sleep and circadian rhythm disruption is frequently associated with neurodegenerative disease, yet it is unclear how the specific pathology in these disorders leads to abnormal rest/activity profiles. To investigate whether the pathological features of lysosomal storage disorders (LSDs) influence the core molecular clock or the circadian behavioural abnormalities reported in some patients, we examined mouse models of Niemann-Pick Type-C (Npc1 mutant, Npc1(nih)) and Sandhoff (Hexb knockout, Hexb(-/-)) disease using wheel-running activity measurement, neuropathology and clock gene expression analysis. Both mutants exhibited regular, entrained rest/activity patterns under light:dark (LD) conditions despite the onset of their respective neurodegenerative phenotypes. A slightly shortened free-running period and changes in Per1 gene expression were observed in Hexb(-/-) mice under constant dark conditions (DD); however, no overt neuropathology was detected in the suprachiasmatic nucleus (SCN). Conversely, despite extensive cholesterol accumulation in the SCN of Npc1(nih) mutants, no circadian disruption was observed under constant conditions. Our results indicate the accumulation of specific metabolites in LSDs may differentially contribute to circadian deregulation at the molecular and behavioural level.
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http://dx.doi.org/10.1016/j.bbr.2015.10.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678117PMC
January 2016

The Regulatory Factor ZFHX3 Modifies Circadian Function in SCN via an AT Motif-Driven Axis.

Cell 2015 Jul;162(3):607-21

MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire OX11 0RD, UK. Electronic address:

We identified a dominant missense mutation in the SCN transcription factor Zfhx3, termed short circuit (Zfhx3(Sci)), which accelerates circadian locomotor rhythms in mice. ZFHX3 regulates transcription via direct interaction with predicted AT motifs in target genes. The mutant protein has a decreased ability to activate consensus AT motifs in vitro. Using RNA sequencing, we found minimal effects on core clock genes in Zfhx3(Sci/+) SCN, whereas the expression of neuropeptides critical for SCN intercellular signaling was significantly disturbed. Moreover, mutant ZFHX3 had a decreased ability to activate AT motifs in the promoters of these neuropeptide genes. Lentiviral transduction of SCN slices showed that the ZFHX3-mediated activation of AT motifs is circadian, with decreased amplitude and robustness of these oscillations in Zfhx3(Sci/+) SCN slices. In conclusion, by cloning Zfhx3(Sci), we have uncovered a circadian transcriptional axis that determines the period and robustness of behavioral and SCN molecular rhythms.
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http://dx.doi.org/10.1016/j.cell.2015.06.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537516PMC
July 2015

The mutant Moonwalker TRPC3 channel links calcium signaling to lipid metabolism in the developing cerebellum.

Hum Mol Genet 2015 Jul 23;24(14):4114-25. Epub 2015 Apr 23.

Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK and

The Moonwalker (Mwk) mouse is a model of dominantly inherited cerebellar ataxia caused by a gain-of-function mutation in the transient receptor potential (TRP) channel TRPC3. Here, we report impairments in dendritic growth and synapse formation early on during Purkinje cell development in the Mwk cerebellum that are accompanied by alterations in calcium signaling. To elucidate the molecular effector pathways that regulate Purkinje cell dendritic arborization downstream of mutant TRPC3, we employed transcriptomic analysis of developing Purkinje cells isolated by laser-capture microdissection. We identified significant gene and protein expression changes in molecules involved in lipid metabolism. Consistently, lipid homeostasis in the Mwk cerebellum was found to be disturbed, and treatment of organotypic cerebellar slices with ceramide significantly improved dendritic outgrowth of Mwk Purkinje cells. These findings provide the first mechanistic insights into the TRPC3-dependent mechanisms, by which activated calcium signaling is coupled to lipid metabolism and the regulation of Purkinje cell development in the Mwk cerebellum.
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http://dx.doi.org/10.1093/hmg/ddv150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476454PMC
July 2015

Oxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutations.

Hum Mol Genet 2015 Jun 19;24(12):3529-44. Epub 2015 Mar 19.

MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of motor neuron-like cells. Mutations in the RNA- and DNA-binding proteins, fused in sarcoma (FUS) and transactive response DNA-binding protein 43 kDa (TDP-43), are responsible for 5-10% of familial and 1% of sporadic ALS cases. Importantly, aggregation of misfolded FUS or TDP-43 is also characteristic of several neurodegenerative disorders in addition to ALS, including frontotemporal lobar degeneration. Moreover, splicing deregulation of FUS and TDP-43 target genes as well as mitochondrial abnormalities are associated with disease-causing FUS and TDP-43 mutants. While progress has been made to understand the functions of these proteins, the exact mechanisms by which FUS and TDP-43 cause ALS remain unknown. Recently, we discovered that, in addition to being up-regulated in spinal cords of ALS patients, the novel protein oxidative resistance 1 (Oxr1) protects neurons from oxidative stress-induced apoptosis. To further understand the function of Oxr1, we present here the first interaction study of the protein. We show that Oxr1 binds to Fus and Tdp-43 and that certain ALS-associated mutations in Fus and Tdp-43 affect their Oxr1-binding properties. We further demonstrate that increasing Oxr1 levels in cells expressing specific Fus and Tdp-43 mutants improves the three main cellular features associated with ALS: cytoplasmic mis-localization and aggregation, splicing changes of a mitochondrial gene and mitochondrial defects. Taken together, these findings suggest that OXR1 may have therapeutic benefits for the treatment of ALS and related neurodegenerative disorders with TDP-43 pathology.
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http://dx.doi.org/10.1093/hmg/ddv104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498158PMC
June 2015

Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis.

Brain 2015 May 9;138(Pt 5):1167-81. Epub 2015 Mar 9.

1 Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3QX, UK

Amyotrophic lateral sclerosis is a devastating neurodegenerative disorder characterized by the progressive loss of spinal motor neurons. While the aetiological mechanisms underlying the disease remain poorly understood, oxidative stress is a central component of amyotrophic lateral sclerosis and contributes to motor neuron injury. Recently, oxidation resistance 1 (OXR1) has emerged as a critical regulator of neuronal survival in response to oxidative stress, and is upregulated in the spinal cord of patients with amyotrophic lateral sclerosis. Here, we tested the hypothesis that OXR1 is a key neuroprotective factor during amyotrophic lateral sclerosis pathogenesis by crossing a new transgenic mouse line that overexpresses OXR1 in neurons with the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Interestingly, we report that overexpression of OXR1 significantly extends survival, improves motor deficits, and delays pathology in the spinal cord and in muscles of SOD1(G93A) mice. Furthermore, we find that overexpression of OXR1 in neurons significantly delays non-cell-autonomous neuroinflammatory response, classic complement system activation, and STAT3 activation through transcriptomic analysis of spinal cords of SOD1(G93A) mice. Taken together, these data identify OXR1 as the first neuron-specific antioxidant modulator of pathogenesis and disease progression in SOD1-mediated amyotrophic lateral sclerosis, and suggest that OXR1 may serve as a novel target for future therapeutic strategies.
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http://dx.doi.org/10.1093/brain/awv039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407188PMC
May 2015
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