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Article ; Online: Energy defects in Huntington's disease: Why "in vivo" evidence matters.

Liot, Géraldine / Valette, Julien / Pépin, Jérémy / Flament, Julien / Brouillet, Emmanuel

Biochemical and biophysical research communications

2017 Volume 483, Issue 4, Page(s) 1084–1095

Abstract: Huntington's disease (HD) is an inherited progressive neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits and psychiatric disturbances. The most striking neuropathological change in HD is the early ... ...

Abstract	Huntington's disease (HD) is an inherited progressive neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits and psychiatric disturbances. The most striking neuropathological change in HD is the early atrophy of the striatum. While the disease progresses, other brain structures also degenerate, including the cerebral cortex. Changes are also seen outside the brain, in particular weight loss/cachexia despite high dietary intake. The disease is caused by an abnormal expansion of a CAG repeat in the gene encoding the huntingtin protein (Htt). This mutation leads to the expression of a poly-glutamine stretch that changes the biological functions of mutant Htt (mHtt). The mechanisms underlying neurodegeneration in HD are not totally elucidated. Here, we discuss recent results obtained in patients, animal and cellular models suggesting that early disturbance in energy metabolism at least in part associated with mitochondrial defects may play a central role, even though all data are not congruent, possibly because most findings were obtained in cell culture systems or using biochemical analyses of post mortem tissues from rodent models. Thus, we put a particular focus on brain imaging studies that could identify biomarkers of energy defects in vivo and would be of prime interest in preclinical and clinical trials testing the efficacy of new therapies targeting energy metabolism in HD.
MeSH term(s)	Animals ; Calcium/metabolism ; Corpus Striatum/metabolism ; Energy Metabolism ; Humans ; Huntington Disease/metabolism ; Membrane Potential, Mitochondrial ; Mice ; Mice, Transgenic ; Mitochondria/metabolism
Chemical Substances	Calcium (SY7Q814VUP)
Language	English
Publishing date	2017-02-19
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2016.09.065
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Article: Zero Echo Time

Baligand, Celine / Barret, Olivier / Tourais, Amélie / Pérot, Jean-Baptiste / Thenadey, Didier / Petit, Fanny / Liot, Géraldine / Gaillard, Marie-Claude / Flament, Julien / Dhenain, Marc / Valette, Julien

Metabolites

2021 Volume 11, Issue 5

Abstract: The cerebral metabolic rate of oxygen consumption ( ... ...

Abstract	The cerebral metabolic rate of oxygen consumption (CMRO
Language	English
Publishing date	2021-04-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662251-8
ISSN	2218-1989
ISSN	2218-1989
DOI	10.3390/metabo11050263
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Article ; Online: The unlikely partnership between LRRK2 and α-synuclein in Parkinson's disease.

Cresto, Noémie / Gardier, Camille / Gubinelli, Francesco / Gaillard, Marie-Claude / Liot, Géraldine / West, Andrew B / Brouillet, Emmanuel

The European journal of neuroscience

2018 Volume 49, Issue 3, Page(s) 339–363

Abstract: Our understanding of the mechanisms underlying Parkinson's disease, the once archetypical nongenetic neurogenerative disorder, has dramatically increased with the identification of α-synuclein and LRRK2 pathogenic mutations. While α-synuclein protein ... ...

Abstract	Our understanding of the mechanisms underlying Parkinson's disease, the once archetypical nongenetic neurogenerative disorder, has dramatically increased with the identification of α-synuclein and LRRK2 pathogenic mutations. While α-synuclein protein composes the aggregates that can spread through much of the brain in disease, LRRK2 encodes a multidomain dual-enzyme distinct from any other protein linked to neurodegeneration. In this review, we discuss emergent datasets from multiple model systems that suggest these unlikely partners do interact in important ways in disease, both within cells that express both LRRK2 and α-synuclein as well as through more indirect pathways that might involve neuroinflammation. Although the link between LRRK2 and disease can be understood in part through LRRK2 kinase activity (phosphotransferase activity), α-synuclein toxicity is multilayered and plausibly interacts with LRRK2 kinase activity in several ways. We discuss common protein interactors like 14-3-3s that may regulate α-synuclein and LRRK2 in disease. Finally, we examine cellular pathways and outcomes common to both mutant α-synuclein expression and LRRK2 activity and points of intersection. Understanding the interplay between these two unlikely partners in disease may provide new therapeutic avenues for PD.
MeSH term(s)	Animals ; Brain/metabolism ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/adverse effects ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism ; Mutation ; Nerve Degeneration/metabolism ; Neurons/metabolism ; Parkinson Disease/genetics ; Parkinson Disease/metabolism ; alpha-Synuclein/adverse effects ; alpha-Synuclein/genetics ; alpha-Synuclein/metabolism
Chemical Substances	alpha-Synuclein ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1)
Language	English
Publishing date	2018-10-24
Publishing country	France
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	645180-9
ISSN	1460-9568 ; 0953-816X
ISSN (online)	1460-9568
ISSN	0953-816X
DOI	10.1111/ejn.14182
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Zs.A 2548: Show issues

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Article: Role of MAPK/ERK in neurotrophin-4 potentiation of necrotic neuronal death.

Lobner, Doug / Liot, Geraldine

Neurochemical research

2004 Volume 29, Issue 12, Page(s) 2303–2309

Abstract: Neurotrophic factors have been proposed for the treatment of a variety of neurological diseases. However, to this point they have failed in clinical trials. One potential problem is that while neurotrophic factors attenuate apoptosis, they have the ... ...

Abstract	Neurotrophic factors have been proposed for the treatment of a variety of neurological diseases. However, to this point they have failed in clinical trials. One potential problem is that while neurotrophic factors attenuate apoptosis, they have the potential to enhance necrosis. In this study we show that neurotrophin-4 (NT-4) attenuated apoptotic neuronal death while potentiating necrotic neuronal death in cortical cultures. The protective effects of NT-4 were not blocked by the mitogen-activated protein kinase kinase (MEK) inhibitors PD098059 or U0126, while the injury potentiation by NT-4 was blocked by these inhibitors. NT-4 stimulated the phosphorylation of ERK1/2 and this phosphorylation was attenuated by U0126 and PD098059. The results indicate a disassociation between the pathway by which NT-4 potentiates necrosis, and that by which it attenuates apoptosis, and suggest that addition of a MEK inhibitor may enhance the beneficial effects of NT-4 in treating complex injuries such as occur in vivo.
MeSH term(s)	Animals ; Butadienes/pharmacology ; Cell Death/drug effects ; Cells, Cultured ; Cyclosporine/toxicity ; Enzyme Activation/drug effects ; Flavonoids/pharmacology ; Immunosuppressive Agents/toxicity ; L-Lactate Dehydrogenase/metabolism ; Mice ; Mitogen-Activated Protein Kinases/antagonists & inhibitors ; Mitogen-Activated Protein Kinases/physiology ; Necrosis ; Nerve Growth Factors/toxicity ; Neurons/drug effects ; Nitriles/pharmacology ; Phosphorylation ; Tetrazolium Salts ; Thiazoles
Chemical Substances	Butadienes ; Flavonoids ; Immunosuppressive Agents ; Nerve Growth Factors ; Nitriles ; Tetrazolium Salts ; Thiazoles ; U 0126 ; Cyclosporine (83HN0GTJ6D) ; L-Lactate Dehydrogenase (EC 1.1.1.27) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; thiazolyl blue (EUY85H477I) ; neurotrophin 4 (P658DCA9XD) ; 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (SJE1IO5E3I)
Language	English
Publishing date	2004-12-15
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	199335-5
ISSN	1573-6903 ; 0364-3190
ISSN (online)	1573-6903
ISSN	0364-3190
DOI	10.1007/s11064-004-7040-4
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Zs.A 1368: Show issues

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Article ; Online: The C-Terminal Domain of LRRK2 with the G2019S Substitution Increases Mutant A53T α-Synuclein Toxicity in Dopaminergic Neurons In Vivo.

International journal of molecular sciences

2021 Volume 22, Issue 13

Abstract: Alpha-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) play crucial roles in Parkinson's disease (PD). They may functionally interact to induce the degeneration of dopaminergic (DA) neurons via mechanisms that are not yet fully understood. We ... ...

Abstract	Alpha-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) play crucial roles in Parkinson's disease (PD). They may functionally interact to induce the degeneration of dopaminergic (DA) neurons via mechanisms that are not yet fully understood. We previously showed that the C-terminal portion of LRRK2 (ΔLRRK2) with the G2019S mutation (ΔLRRK2
MeSH term(s)	Animals ; Disease Models, Animal ; Dopaminergic Neurons/metabolism ; Dopaminergic Neurons/pathology ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism ; Mutant Proteins/genetics ; Mutant Proteins/metabolism ; Mutation ; Protein Domains ; Rats ; alpha-Synuclein/genetics ; alpha-Synuclein/metabolism
Chemical Substances	Mutant Proteins ; SNCA protein, human ; alpha-Synuclein ; LRRK2 protein, human (EC 2.7.11.1) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1)
Language	English
Publishing date	2021-06-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22136760
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Article ; Online: Mutant Huntingtin alters retrograde transport of TrkB receptors in striatal dendrites.

Liot, Géraldine / Zala, Diana / Pla, Patrick / Mottet, Guillaume / Piel, Matthieu / Saudou, Frédéric

The Journal of neuroscience : the official journal of the Society for Neuroscience

2013 Volume 33, Issue 15, Page(s) 6298–6309

Abstract: Huntingtin (HTT), the protein mutated in Huntington's disease (HD), controls transport of the neurotrophin, brain-derived neurotrophic factor (BDNF), within corticostriatal neurons. Transport and delivery of BDNF to the striatum are reduced in disease, ... ...

Abstract	Huntingtin (HTT), the protein mutated in Huntington's disease (HD), controls transport of the neurotrophin, brain-derived neurotrophic factor (BDNF), within corticostriatal neurons. Transport and delivery of BDNF to the striatum are reduced in disease, which contributes to striatal neuron degeneration. BDNF released by cortical neurons activates TrkB receptors at striatal dendrites to promote striatum survival. However, it remains to be determined whether transport of TrkB, the BDNF receptor, depends on HTT and whether such transport is altered in mutant situation. Here we show that TrkB binds to and colocalizes with HTT and dynein. Silencing HTT reduces vesicular transport of TrkB in striatal neurons. In HD, the polyQ expansion in HTT alters the binding of TrkB-containing vesicles to microtubules and reduces transport. Using a combination of microfluidic devices that isolate dendrites from cell bodies and BDNF coupled to quantum dots, we selectively analyzed TrkB retrograde transport in response to BDNF stimulation at dendrite terminals. We show that the retrograde transport of TrkB vesicles within striatal dendrites and the BDNF/TrkB-induced signaling through ERK phosphorylation and c-fos induction are decreased in neurons from an HD mouse model. Together, our findings demonstrate that HTT is a crucial regulator of TrkB trafficking. Transport defects in HD are not restricted to BDNF transport in cortical neurons but also affect trafficking of its ligand-bound receptor in the striatal neurons. This transport alteration may further impair BDNF-TrkB survival signaling within the corticostriatal connection that is most affected in HD.
MeSH term(s)	Animals ; Brain-Derived Neurotrophic Factor/metabolism ; Brain-Derived Neurotrophic Factor/pharmacology ; Cell Line ; Corpus Striatum/metabolism ; Dendrites/metabolism ; Disease Models, Animal ; Dyneins/metabolism ; Huntingtin Protein ; Huntington Disease/genetics ; Huntington Disease/metabolism ; Mice ; Microtubules/metabolism ; Mutation/genetics ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Primary Cell Culture ; Protein Transport ; Rats ; Receptor, trkB/metabolism ; Signal Transduction/genetics ; Transport Vesicles/genetics ; Transport Vesicles/metabolism
Chemical Substances	Brain-Derived Neurotrophic Factor ; Htt protein, mouse ; Huntingtin Protein ; Nerve Tissue Proteins ; Nuclear Proteins ; Receptor, trkB (EC 2.7.10.1) ; Dyneins (EC 3.6.4.2)
Language	English
Publishing date	2013-04-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.2033-12.2013
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Article ; Online: Multi-omics comparison of malignant and normal uveal melanocytes reveals molecular features of uveal melanoma.

Gentien, David / Saberi-Ansari, Elnaz / Servant, Nicolas / Jolly, Ariane / de la Grange, Pierre / Némati, Fariba / Liot, Géraldine / Saule, Simon / Teissandier, Aurélie / Bourc'his, Deborah / Girard, Elodie / Wong, Jennifer / Masliah-Planchon, Julien / Narmanli, Erkan / Liu, Yuanlong / Torun, Emma / Goulancourt, Rebecca / Rodrigues, Manuel / Gaudé, Laure Villoing /

Cell reports

2023 Volume 42, Issue 9, Page(s) 113132

Abstract: Uveal melanoma (UM) is a rare cancer resulting from the transformation of melanocytes in the uveal tract. Integrative analysis has identified four molecular and clinical subsets of UM. To improve our molecular understanding of UM, we performed extensive ... ...

Abstract	Uveal melanoma (UM) is a rare cancer resulting from the transformation of melanocytes in the uveal tract. Integrative analysis has identified four molecular and clinical subsets of UM. To improve our molecular understanding of UM, we performed extensive multi-omics characterization comparing two aggressive UM patient-derived xenograft models with normal choroidal melanocytes, including DNA optical mapping, specific histone modifications, and DNA topology analysis using Hi-C. Our gene expression and cytogenetic analyses suggest that genomic instability is a hallmark of UM. We also identified a recurrent deletion in the BAP1 promoter resulting in loss of expression and associated with high risk of metastases in UM patients. Hi-C revealed chromatin topology changes associated with the upregulation of PRAME, an independent prognostic biomarker in UM, and a potential therapeutic target. Our findings illustrate how multi-omics approaches can improve our understanding of tumorigenesis and reveal two distinct mechanisms of gene expression dysregulation in UM.
MeSH term(s)	Humans ; Multiomics ; Melanoma/pathology ; Melanocytes/metabolism ; DNA ; Antigens, Neoplasm/genetics
Chemical Substances	DNA (9007-49-2) ; PRAME protein, human ; Antigens, Neoplasm
Language	English
Publishing date	2023-09-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.113132
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Article ; Online: Vesicular glycolysis provides on-board energy for fast axonal transport.

Zala, Diana / Hinckelmann, Maria-Victoria / Yu, Hua / Lyra da Cunha, Marcel Menezes / Liot, Géraldine / Cordelières, Fabrice P / Marco, Sergio / Saudou, Frédéric

Cell

2013 Volume 152, Issue 3, Page(s) 479–491

Abstract: Fast axonal transport (FAT) requires consistent energy over long distances to fuel the molecular motors that transport vesicles. We demonstrate that glycolysis provides ATP for the FAT of vesicles. Although inhibiting ATP production from mitochondria did ...

Abstract	Fast axonal transport (FAT) requires consistent energy over long distances to fuel the molecular motors that transport vesicles. We demonstrate that glycolysis provides ATP for the FAT of vesicles. Although inhibiting ATP production from mitochondria did not affect vesicles motility, pharmacological or genetic inhibition of the glycolytic enzyme GAPDH reduced transport in cultured neurons and in Drosophila larvae. GAPDH localizes on vesicles via a huntingtin-dependent mechanism and is transported on fast-moving vesicles within axons. Purified motile vesicles showed GAPDH enzymatic activity and produced ATP. Finally, we show that vesicular GAPDH is necessary and sufficient to provide on-board energy for fast vesicular transport. Although detaching GAPDH from vesicles reduced transport, targeting GAPDH to vesicles was sufficient to promote FAT in GAPDH deficient neurons. This specifically localized glycolytic machinery may supply constant energy, independent of mitochondria, for the processive movement of vesicles over long distances in axons.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Animals ; Axonal Transport ; Axons/metabolism ; Brain/cytology ; Cells, Cultured ; Drosophila melanogaster/growth & development ; Drosophila melanogaster/metabolism ; Glyceraldehyde-3-Phosphate Dehydrogenases/metabolism ; Glycolysis ; Mice ; Mitochondria/metabolism ; Neurons/metabolism ; Rats
Chemical Substances	Adenosine Triphosphate (8L70Q75FXE) ; Glyceraldehyde-3-Phosphate Dehydrogenases (EC 1.2.1.-)
Language	English
Publishing date	2013-01-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2012.12.029
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Zs.A 1167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: The mTOR inhibitor Everolimus synergizes with the PI3K inhibitor GDC0941 to enhance anti-tumor efficacy in uveal melanoma.

Amirouchene-Angelozzi, Nabil / Frisch-Dit-Leitz, Estelle / Carita, Guillaume / Dahmani, Ahmed / Raymondie, Chloé / Liot, Géraldine / Gentien, David / Némati, Fariba / Decaudin, Didier / Roman-Roman, Sergio / Schoumacher, Marie

Oncotarget

2016 Volume 7, Issue 17, Page(s) 23633–23646

Abstract: Uveal melanoma (UM) is the most frequent malignant ocular tumor in adults. While the primary tumor is efficiently treated by surgery and/or radiotherapy, about one third of UM patients develop metastases, for which no effective treatment is currently ... ...

Abstract	Uveal melanoma (UM) is the most frequent malignant ocular tumor in adults. While the primary tumor is efficiently treated by surgery and/or radiotherapy, about one third of UM patients develop metastases, for which no effective treatment is currently available. The PKC, MAPK and PI3K/AKT/mTOR signaling cascades have been shown to be associated with tumor growth. However, none of the compounds against those pathways results in tumor regression when used as single agents. To identify more effective therapeutic strategies for UM patients, we performed a combination screen using seven targeted agents inhibiting PKC, MEK, AKT, PI3K and mTOR in a panel of ten UM cell lines, representative of the UM disease. We identified a strong synergy between the mTOR inhibitor Everolimus and the PI3K inhibitor GDC0941. This combination resulted in an increase in apoptosis in several UM cell lines compared to monotherapies and enhanced the anti-tumor effect of each single agent in two patient-derived xenografts. Furthermore, we showed that the synergism between the two drugs was associated with the relief by GDC0491 of a reactivation of AKT induced by Everolimus. Altogether, our results highlight a novel and effective combination strategy, which could be beneficial for UM patients.
Language	English
Publishing date	2016-04-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.8054
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Article ; Online: Sulfheme formation during homocysteine S-oxygenation by catalase in cancers and neurodegenerative diseases.

Padovani, Dominique / Hessani, Assia / Castillo, Francine T / Liot, Géraldine / Andriamihaja, Mireille / Lan, Annaïg / Pilati, Camilla / Blachier, François / Sen, Suvajit / Galardon, Erwan / Artaud, Isabelle

Nature communications

2016 Volume 7, Page(s) 13386

Abstract: Accumulating evidence suggests that abnormal levels of homocysteine are associated with vascular dysfunctions, cancer cell proliferation and various neurodegenerative diseases. With respect to the latter, a perturbation of transition metal homeostasis ... ...

Abstract	Accumulating evidence suggests that abnormal levels of homocysteine are associated with vascular dysfunctions, cancer cell proliferation and various neurodegenerative diseases. With respect to the latter, a perturbation of transition metal homeostasis and an inhibition of catalase bioactivity have been reported. Herein, we report on some of the molecular bases for the cellular toxicity of homocysteine and demonstrate that it induces the formation of sulfcatalase, an irreversible inactive state of the enzyme, without the intervention of hydrogen sulfide. Initially, homocysteine reacts with native catalase and/or redox-active transition metal ions to generate thiyl radicals that mediate compound II formation, a temporarily inactive state of the enzyme. Then, the ferryl centre of compound II intervenes into the unprecedented S-oxygenation of homocysteine to engender the corresponding sulfenic acid species that further participates into the prosthetic heme modification through the formation of an unusual Fe(II) sulfonium. In addition, our ex cellulo studies performed on cancer cells, models of neurodegenerative diseases and ulcerative colitis suggest the likelihood of this scenario in a subset of cancer cells, as well as in a cellular model of Parkinson's disease. Our findings expand the repertoire of heme modifications promoted by biological compounds and point out another deleterious trait of disturbed homocysteine levels that could participate in the aetiology of these diseases.
MeSH term(s)	Animals ; Catalase/antagonists & inhibitors ; Catalase/metabolism ; Cell Line, Tumor ; Chromatography, High Pressure Liquid ; Enzyme Activation/drug effects ; Heme/analogs & derivatives ; Heme/chemistry ; Heme/metabolism ; Homocysteine/metabolism ; Hydrogen Sulfide/metabolism ; Iron/metabolism ; Male ; Mass Spectrometry ; Mice, Inbred C57BL ; Neoplasms/metabolism ; Neoplasms/pathology ; Neurodegenerative Diseases/metabolism ; Oxidation-Reduction ; Oxygen/metabolism ; Sulfhydryl Compounds/pharmacology
Chemical Substances	Sulfhydryl Compounds ; Homocysteine (0LVT1QZ0BA) ; sulfheme (105253-67-6) ; Heme (42VZT0U6YR) ; Iron (E1UOL152H7) ; Catalase (EC 1.11.1.6) ; Oxygen (S88TT14065) ; Hydrogen Sulfide (YY9FVM7NSN)
Language	English
Publishing date	2016-11-16
Publishing country	England
Document type	Journal Article
ISSN	2041-1723
ISSN (online)	2041-1723
DOI	10.1038/ncomms13386
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