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Article: Neurotrophin receptοrs, gamma-secretase inhibitors, and neurodegeneration of basal forebrain cholinergic neurons.

Vilar, Marçal

2021 Volume 17, Issue 7, Page(s) 1493–1494

Language	English
Publishing date	2021-12-16
Publishing country	India
Document type	Journal Article
ZDB-ID	2388460-5
ISSN	1876-7958 ; 1673-5374
ISSN (online)	1876-7958
ISSN	1673-5374
DOI	10.4103/1673-5374.330607
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Article ; Online: Identification of a guanine-specific pocket in the protein N of SARS-CoV-2.

Rafael Ciges-Tomas, J / Franco, María Luisa / Vilar, Marçal

Communications biology

2022 Volume 5, Issue 1, Page(s) 711

Abstract: The SARS-CoV-2 nucleocapsid protein (N) is responsible for RNA binding. Here we report the crystal structure of the C-terminal domain ( ... ...

Abstract	The SARS-CoV-2 nucleocapsid protein (N) is responsible for RNA binding. Here we report the crystal structure of the C-terminal domain (N
MeSH term(s)	COVID-19 ; Guanine ; Humans ; Nucleocapsid Proteins/chemistry ; Nucleocapsid Proteins/genetics ; Nucleocapsid Proteins/metabolism ; RNA, Viral/metabolism ; SARS-CoV-2/genetics
Chemical Substances	Nucleocapsid Proteins ; RNA, Viral ; Guanine (5Z93L87A1R)
Language	English
Publishing date	2022-07-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-022-03647-8
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Article ; Online: Identification of a guanine-specific pocket in the protein N of SARS-CoV-2

Ciges-Tomas, Rafael / Franco, Maria Luisa / Vilar, Marcal

bioRxiv

Abstract: The SARS-CoV-2 nucleocapsid protein (N) is responsible for RNA binding. Here we report the crystal structure of the C-terminal domain (NCTD) in open and closed conformations and in complex with guanine triphosphate, GTP. The crystal structure and ... ...

Abstract	The SARS-CoV-2 nucleocapsid protein (N) is responsible for RNA binding. Here we report the crystal structure of the C-terminal domain (NCTD) in open and closed conformations and in complex with guanine triphosphate, GTP. The crystal structure and biochemical studies reveals a specific interaction between the guanine, a nucleotide enriched in the packaging signals regions of coronaviruses, and a highly conserved tryptophan residue (W330). In addition, EMSA assays with SARS-CoV-2 derived RNA hairpin loops from a putative viral packaging sequence showed the preference interaction of the N-CTD to RNA oligonucleotides containing G and the loss of the specificity in the mutant W330A. Here we propose that this interaction may facilitate the viral assembly process. In summary we have identified a specific guanine-binding pocket in the N protein that may be used to design viral assembly inhibitors.
Keywords	covid19
Language	English
Publishing date	2022-06-21
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.06.21.496991
Database	COVID19

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Article: Regulation of Neurogenesis by Neurotrophins during Adulthood: Expected and Unexpected Roles.

Vilar, Marçal / Mira, Helena

Frontiers in neuroscience

2016 Volume 10, Page(s) 26

Abstract: The subventricular zone (SVZ) of the anterolateral ventricle and the subgranular zone (SGZ) of the hippocampal dentate gyrus are the two main regions of the adult mammalian brain in which neurogenesis is maintained throughout life. Because alterations in ...

Abstract	The subventricular zone (SVZ) of the anterolateral ventricle and the subgranular zone (SGZ) of the hippocampal dentate gyrus are the two main regions of the adult mammalian brain in which neurogenesis is maintained throughout life. Because alterations in adult neurogenesis appear to be a common hallmark of different neurodegenerative diseases, understanding the molecular mechanisms controlling adult neurogenesis is a focus of active research. Neurotrophic factors are a family of molecules that play critical roles in the survival and differentiation of neurons during development and in the control of neural plasticity in the adult. Several neurotrophins and neurotrophin receptors have been implicated in the regulation of adult neurogenesis at different levels. Here, we review the current understanding of neurotrophin modulation of adult neurogenesis in both the SVZ and SGZ. We compile data supporting a variety of roles for neurotrophins/neurotrophin receptors in different scenarios, including both expected and unexpected functions.
Language	English
Publishing date	2016-02-09
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2016.00026
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Article ; Online: Intrinsically disordered regions couple the ligand binding and kinase activation of Trk neurotrophin receptors.

Kot, Erik F / Franco, María L / Vasilieva, Ekaterina V / Shabalkina, Alexandra V / Arseniev, Alexander S / Goncharuk, Sergey A / Mineev, Konstantin S / Vilar, Marçal

iScience

2022 Volume 25, Issue 6, Page(s) 104348

Abstract: Receptor tyrosine kinases (RTKs) are key players in development and several diseases. Understanding the molecular mechanism of RTK activation by its ligand could lead to the design of new RTK inhibitors. How the extracellular domain is coupled to the ... ...

Abstract	Receptor tyrosine kinases (RTKs) are key players in development and several diseases. Understanding the molecular mechanism of RTK activation by its ligand could lead to the design of new RTK inhibitors. How the extracellular domain is coupled to the intracellular kinase domain is a matter of debate. Ligand-induced dimerization and ligand-induced conformational change of pre-formed dimers are two of the most proposed models. Recently we proposed that TrkA, the RTK for nerve growth factor (NGF), is activated by rotation of the transmembrane domain (TMD) pre-formed dimers upon NGF binding. However, one of the unsolved issues is how the ligand binding is conformationally coupled to the TMD rotation if unstructured extracellular juxtamembrane (eJTM) regions separate them. Here we use nuclear magnetic resonance in bicelles and functional studies to demonstrate that eJTM regions from the Trk family are intrinsically disordered and couple the ligand-binding domains and TMDs possibly via the interaction with NGF.
Language	English
Publishing date	2022-05-03
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2022.104348
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Article ; Online: Forkhead transcription factor FKH-8 cooperates with RFX in the direct regulation of sensory cilia in

Brocal-Ruiz, Rebeca / Esteve-Serrano, Ainara / Mora-Martínez, Carlos / Franco-Rivadeneira, Maria Luisa / Swoboda, Peter / Tena, Juan J / Vilar, Marçal / Flames, Nuria

eLife

2023 Volume 12

Abstract: Cilia, either motile or non-motile (a.k.a primary or sensory), are complex evolutionarily conserved eukaryotic structures composed of hundreds of proteins required for their assembly, structure and function that are collectively known as the ciliome. ... ...

Abstract	Cilia, either motile or non-motile (a.k.a primary or sensory), are complex evolutionarily conserved eukaryotic structures composed of hundreds of proteins required for their assembly, structure and function that are collectively known as the ciliome. Ciliome gene mutations underlie a group of pleiotropic genetic diseases known as ciliopathies. Proper cilium function requires the tight coregulation of ciliome gene transcription, which is only fragmentarily understood. RFX transcription factors (TF) have an evolutionarily conserved role in the direct activation of ciliome genes both in motile and non-motile cilia cell-types. In vertebrates, FoxJ1 and FoxN4 Forkhead (FKH) TFs work with RFX in the direct activation of ciliome genes, exclusively in motile cilia cell-types. No additional TFs have been described to act together with RFX in primary cilia cell-types in any organism. Here we describe FKH-8, a FKH TF, as a direct regulator of the sensory ciliome genes in
MeSH term(s)	Animals ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/genetics ; Caenorhabditis elegans Proteins/metabolism ; Cilia/metabolism ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; Sensory Receptor Cells/physiology
Chemical Substances	Caenorhabditis elegans Proteins ; Forkhead Transcription Factors ; fkh-8 protein, C elegans
Language	English
Publishing date	2023-07-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.89702
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Article ; Online: Apolipoprotein E ε4 triggers neurotoxicity via cholesterol accumulation, acetylcholine dyshomeostasis, and PKCε mislocalization in cholinergic neuronal cells.

Piccarducci, Rebecca / Giacomelli, Chiara / Bertilacchi, Maria Sofia / Benito-Martinez, Andrea / Di Giorgi, Nicoletta / Daniele, Simona / Signore, Giovanni / Rocchiccioli, Silvia / Vilar, Marçal / Marchetti, Laura / Martini, Claudia

Biochimica et biophysica acta. Molecular basis of disease

2023 Volume 1869, Issue 7, Page(s) 166793

Abstract: The Apolipoprotein E (ApoE) has been known to regulate cholesterol and β-amyloid (Aβ) production, redistribution, and elimination, in the central nervous system (CNS). The ApoE ε4 polymorphic variant leads to impaired brain cholesterol homeostasis and ... ...

Abstract	The Apolipoprotein E (ApoE) has been known to regulate cholesterol and β-amyloid (Aβ) production, redistribution, and elimination, in the central nervous system (CNS). The ApoE ε4 polymorphic variant leads to impaired brain cholesterol homeostasis and amyloidogenic pathway, thus representing the major risk factor for Alzheimer's Disease (AD). Currently, less is known about the molecular mechanisms connecting ApoE ε4-related cholesterol metabolism and cholinergic system degeneration, one of the main AD pathological features. Herein, in vitro cholinergic neuron models were developed in order to study ApoE neuronal expression and investigate the possible interplay between cholesterol metabolism and cholinergic pathway impairment prompted by ε4 isoform. Particularly, alterations specifically occurring in ApoE ε4-carrying neurons (i.e. increased intracellular ApoE, amyloid precursor protein (APP) and Aβ levels, elevated apoptosis, and reduced cell survival) were recapitulated. ApoE ε4 expression was found to increase intracellular cholesterol accumulation, by regulating the related gene expression, while reducing cholesterol precursor acetyl-CoA, which in turn fuels the acetylcholine (ACh) synthesis route. In parallel, although the ACh intracellular signalling was activated, as demonstrated by the boosted extracellular ACh as well as increased IP
MeSH term(s)	Humans ; Acetylcholine ; Alzheimer Disease/metabolism ; Apolipoprotein E4/genetics ; Apolipoproteins E/genetics ; Cholesterol ; Cholinergic Agents ; Neurons/metabolism ; Protein Kinase C-epsilon/metabolism
Chemical Substances	Acetylcholine (N9YNS0M02X) ; Apolipoprotein E4 ; Apolipoproteins E ; Cholesterol (97C5T2UQ7J) ; Cholinergic Agents ; ApoE protein, human ; Protein Kinase C-epsilon (EC 2.7.11.13)
Language	English
Publishing date	2023-06-17
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbadis.2023.166793
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Article: Cholinergic neurodegeneration and cholesterol metabolism dysregulation by constitutive p75

Comaposada-Baró, Raquel / Benito-Martínez, Andrea / Escribano-Saiz, Juan Julian / Franco, María Luisa / Ceccarelli, Lorenzo / Calatayud-Baselga, Isabel / Mira, Helena / Vilar, Marçal

Frontiers in molecular neuroscience

2023 Volume 16, Page(s) 1237458

Abstract: Degeneration of basal forebrain cholinergic neurons (BFCNs) is a hallmark of Alzheimer's disease (AD). However, few mouse models of AD recapitulate the neurodegeneration of the cholinergic system. The p75 neurotrophin receptor, ... ...

Abstract	Degeneration of basal forebrain cholinergic neurons (BFCNs) is a hallmark of Alzheimer's disease (AD). However, few mouse models of AD recapitulate the neurodegeneration of the cholinergic system. The p75 neurotrophin receptor, p75
Language	English
Publishing date	2023-10-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2023.1237458
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Article ; Online: TrkA-mediated endocytosis of p75-CTF prevents cholinergic neuron death upon γ-secretase inhibition.

Franco, María Luisa / García-Carpio, Irmina / Comaposada-Baró, Raquel / Escribano-Saiz, Juan J / Chávez-Gutiérrez, Lucía / Vilar, Marçal

Life science alliance

2021 Volume 4, Issue 4

Abstract: γ-secretase inhibitors (GSI) were developed to reduce the generation of Aβ peptide to find new Alzheimer's disease treatments. Clinical trials on Alzheimer's disease patients, however, showed several side effects that worsened the cognitive symptoms of ... ...

Abstract	γ-secretase inhibitors (GSI) were developed to reduce the generation of Aβ peptide to find new Alzheimer's disease treatments. Clinical trials on Alzheimer's disease patients, however, showed several side effects that worsened the cognitive symptoms of the treated patients. The observed side effects were partially attributed to Notch signaling. However, the effect on other γ-secretase substrates, such as the p75 neurotrophin receptor (p75NTR) has not been studied in detail. p75NTR is highly expressed in the basal forebrain cholinergic neurons (BFCNs) during all life. Here, we show that GSI treatment induces the oligomerization of p75CTF leading to the cell death of BFCNs, and that this event is dependent on TrkA activity. The oligomerization of p75CTF requires an intact cholesterol recognition sequence (CRAC) and the constitutive binding of TRAF6, which activates the JNK and p38 pathways. Remarkably, TrkA rescues from cell death by a mechanism involving the endocytosis of p75CTF. These results suggest that the inhibition of γ-secretase activity in aged patients, where the expression of TrkA in the BFCNs is already reduced, could accelerate cholinergic dysfunction and promote neurodegeneration.
MeSH term(s)	Alzheimer Disease/etiology ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Amino Acid Motifs ; Amyloid Precursor Protein Secretases/antagonists & inhibitors ; Amyloid Precursor Protein Secretases/metabolism ; Cell Death/drug effects ; Cholinergic Neurons/drug effects ; Cholinergic Neurons/metabolism ; Cycloheximide/pharmacology ; Endocytosis ; Humans ; Ligands ; MAP Kinase Signaling System ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Multimerization/drug effects ; Proteolysis ; Receptor, Nerve Growth Factor/chemistry ; Receptor, Nerve Growth Factor/metabolism ; Receptor, trkA/metabolism
Chemical Substances	Ligands ; NTRK1 protein, human ; Receptor, Nerve Growth Factor ; Cycloheximide (98600C0908) ; Receptor, trkA (EC 2.7.10.1) ; Amyloid Precursor Protein Secretases (EC 3.4.-)
Language	English
Publishing date	2021-02-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202000844
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Article ; Online: Beyond genetics: Deciphering the impact of missense variants in CAD deficiency.

Del Caño-Ochoa, Francisco / Ng, Bobby G / Rubio-Del-Campo, Antonio / Mahajan, Sonal / Wilson, Matthew P / Vilar, Marçal / Rymen, Daisy / Sánchez-Pintos, Paula / Kenny, Joanna / Ley Martos, Myriam / Campos, Teresa / Wortmann, Saskia B / Freeze, Hudson H / Ramón-Maiques, Santiago

Journal of inherited metabolic disease

2023 Volume 46, Issue 6, Page(s) 1170–1185

Abstract: CAD is a large, 2225 amino acid multienzymatic protein required for de novo pyrimidine biosynthesis. Pathological CAD variants cause a developmental and epileptic encephalopathy which is highly responsive to uridine supplements. CAD deficiency is ... ...

Abstract	CAD is a large, 2225 amino acid multienzymatic protein required for de novo pyrimidine biosynthesis. Pathological CAD variants cause a developmental and epileptic encephalopathy which is highly responsive to uridine supplements. CAD deficiency is difficult to diagnose because symptoms are nonspecific, there is no biomarker, and the protein has over 1000 known variants. To improve diagnosis, we assessed the pathogenicity of 20 unreported missense CAD variants using a growth complementation assay that identified 11 pathogenic variants in seven affected individuals; they would benefit from uridine treatment. We also tested nine variants previously reported as pathogenic and confirmed the damaging effect of seven. However, we reclassified two variants as likely benign based on our assay, which is consistent with their long-term follow-up with uridine. We found that several computational methods are unreliable predictors of pathogenic CAD variants, so we extended the functional assay results by studying the impact of pathogenic variants at the protein level. We focused on CAD's dihydroorotase (DHO) domain because it accumulates the largest density of damaging missense changes. The atomic-resolution structures of eight DHO pathogenic variants, combined with functional and molecular dynamics analyses, provided a comprehensive structural and functional understanding of the activity, stability, and oligomerization of CAD's DHO domain. Combining our functional and protein structural analysis can help refine clinical diagnostic workflow for CAD variants in the genomics era.
MeSH term(s)	Humans ; Dihydroorotase/chemistry ; Dihydroorotase/genetics ; Dihydroorotase/metabolism ; Mutation, Missense ; Proteins ; Uridine
Chemical Substances	Dihydroorotase (EC 3.5.2.3) ; Proteins ; Uridine (WHI7HQ7H85) ; CAD trifunctional enzyme
Language	English
Publishing date	2023-09-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	438341-2
ISSN	1573-2665 ; 0141-8955
ISSN (online)	1573-2665
ISSN	0141-8955
DOI	10.1002/jimd.12667
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