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Article: Efficacy of Vafidemstat in Experimental Autoimmune Encephalomyelitis Highlights the KDM1A/RCOR1/HDAC Epigenetic Axis in Multiple Sclerosis.

Cavalcanti, Fernando / Gonzalez-Rey, Elena / Delgado, Mario / Falo, Clara P / Mestre, Leyre / Guaza, Carmen / O'Valle, Francisco / Lufino, Michele M P / Xaus, Jordi / Mascaró, Cristina / Lunardi, Serena / Sacilotto, Natalia / Dessanti, Paola / Rotllant, David / Navarro, Xavier / Herrando-Grabulosa, Mireia / Buesa, Carlos / Maes, Tamara

Pharmaceutics

2022 Volume 14, Issue 7

Abstract: Lysine specific demethylase 1 (LSD1; also known as KDM1A), is an epigenetic modulator that modifies the histone methylation status. KDM1A forms a part of protein complexes that regulate the expression of genes involved in the onset and progression of ... ...

Abstract	Lysine specific demethylase 1 (LSD1; also known as KDM1A), is an epigenetic modulator that modifies the histone methylation status. KDM1A forms a part of protein complexes that regulate the expression of genes involved in the onset and progression of diseases such as cancer, central nervous system (CNS) disorders, viral infections, and others. Vafidemstat (ORY-2001) is a clinical stage inhibitor of KDM1A in development for the treatment of neurodegenerative and psychiatric diseases. However, the role of ORY-2001 targeting KDM1A in neuroinflammation remains to be explored. Here, we investigated the effect of ORY-2001 on immune-mediated and virus-induced encephalomyelitis, two experimental models of multiple sclerosis and neuronal damage. Oral administration of ORY-2001 ameliorated clinical signs, reduced lymphocyte egress and infiltration of immune cells into the spinal cord, and prevented demyelination. Interestingly, ORY-2001 was more effective and/or faster acting than a sphingosine 1-phosphate receptor antagonist in the effector phase of the disease and reduced the inflammatory gene expression signature characteristic ofEAE in the CNS of mice more potently. In addition, ORY-2001 induced gene expression changes concordant with a potential neuroprotective function in the brain and spinal cord and reduced neuronal glutamate excitotoxicity-derived damage in explants. These results pointed to ORY-2001 as a promising CNS epigenetic drug able to target neuroinflammatory and neurodegenerative diseases and provided preclinical support for the subsequent design of early-stage clinical trials.
Language	English
Publishing date	2022-07-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics14071420
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Article ; Online: Advances in the development of histone lysine demethylase inhibitors.

Maes, Tamara / Carceller, Elena / Salas, Jordi / Ortega, Alberto / Buesa, Carlos

Current opinion in pharmacology

2015 Volume 23, Page(s) 52–60

Abstract: The covalent modification of histones is closely associated with regulation of gene transcription. Chromatin modifications have been suggested to represent an epigenetic code that is dynamically 'written' and 'erased' by specialized proteins, and 'read', ...

Abstract	The covalent modification of histones is closely associated with regulation of gene transcription. Chromatin modifications have been suggested to represent an epigenetic code that is dynamically 'written' and 'erased' by specialized proteins, and 'read', or interpreted, by proteins that translate the code into gene expression changes. Initially thought to be an irreversible process, histone methylation is now known to be reversed by demethylases, FAD dependent amineoxidases and by iron(II)-alpha-ketoglutarate dependent deoxygenases of the Jumonji family. Altered histone demethylase activities have been associated with human disease, including cancer. The first wave of novel investigational drugs directed against KDM1A has recently entered the clinic, and the first specific inhibitor targeting a Jumonji KDM is advancing in preclinical regulatory studies.
MeSH term(s)	Animals ; Benzoates/administration & dosage ; Benzoates/chemistry ; Cyclopropanes/administration & dosage ; Cyclopropanes/chemistry ; Enzyme Inhibitors/administration & dosage ; Enzyme Inhibitors/chemistry ; Histone Demethylases/antagonists & inhibitors ; Histone Demethylases/chemistry ; Humans ; Neoplasms/drug therapy ; Neoplasms/enzymology
Chemical Substances	Benzoates ; Cyclopropanes ; Enzyme Inhibitors ; GSK2879552 ; Histone Demethylases (EC 1.14.11.-) ; KDM1A protein, human (EC 1.5.-)
Language	English
Publishing date	2015-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2037057-X
ISSN	1471-4973 ; 1471-4892
ISSN (online)	1471-4973
ISSN	1471-4892
DOI	10.1016/j.coph.2015.05.009
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Article ; Online: Comprehensive

Sacilotto, Natalia / Dessanti, Paola / Lufino, Michele M P / Ortega, Alberto / Rodríguez-Gimeno, Alejandra / Salas, Jordi / Maes, Tamara / Buesa, Carlos / Mascaró, Cristina / Soliva, Robert

ACS pharmacology & translational science

2021 Volume 4, Issue 6, Page(s) 1818–1834

Abstract: Lysine-specific demethylase 1 (LSD1 or KDM1A) is a chromatin modifying enzyme playing a key role in the cell cycle and cell differentiation and proliferation through the demethylation of histones and nonhistone substrates. In addition to its enzymatic ... ...

Abstract	Lysine-specific demethylase 1 (LSD1 or KDM1A) is a chromatin modifying enzyme playing a key role in the cell cycle and cell differentiation and proliferation through the demethylation of histones and nonhistone substrates. In addition to its enzymatic activity, LSD1 plays a fundamental scaffolding role as part of transcription silencing complexes such as rest co-repressor (CoREST) and nucleosome remodeling and deacetylase (NuRD). A host of classical amine oxidase inhibitors such as tranylcypromine, pargyline, and phenelzine together with LSD1 tool compounds such as SP-2509 and GSK-LSD1 have been extensively utilized in LSD1 mechanistic cancer studies. Additionally, several optimized new chemical entities have reached clinical trials in oncology such as ORY-1001 (iadademstat), GSK2879552, SP-2577 (seclidemstat), IMG-7289 (bomedemstat), INCB059872, and CC-90011 (pulrodemstat). Despite this, no single study exists that characterizes them all under the same experimental conditions, preventing a clear interpretation of published results. Herein, we characterize the whole LSD1 small molecule compound class as inhibitors of LSD1 catalytic activity, disruptors of SNAIL/GFI1 (SNAG)-scaffolding protein-protein interactions, inducers of cell differentiation, and potential anticancer treatments for hematological and solid tumors to yield an updated, unified perspective of this field. Our results highlight significant differences in potency and selectivity among the clinical compounds with iadademstat being the most potent and reveal that most of the tool compounds have very low activity and selectivity, suggesting some conclusions derived from their use should be taken with caution.
Language	English
Publishing date	2021-11-12
Publishing country	United States
Document type	Journal Article
ISSN	2575-9108
ISSN (online)	2575-9108
DOI	10.1021/acsptsci.1c00223
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Article ; Online: First-in-Human Randomized Trial to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the KDM1A Inhibitor Vafidemstat.

Antonijoan, Rosa María / Ferrero-Cafiero, Juan Manuel / Coimbra, Jimena / Puntes, Montse / Martínez-Colomer, Joan / Arévalo, María Isabel / Mascaró, Cristina / Molinero, Cesar / Buesa, Carlos / Maes, Tamara

CNS drugs

2021 Volume 35, Issue 3, Page(s) 331–344

Abstract: Background: Vafidemstat, an inhibitor of the histone lysine-specific demethylase KDM1A, corrects cognition deficits and behavior alterations in rodent models. Here, we report the results from the first-in-human trial of vafidemstat in healthy young and ... ...

Abstract	Background: Vafidemstat, an inhibitor of the histone lysine-specific demethylase KDM1A, corrects cognition deficits and behavior alterations in rodent models. Here, we report the results from the first-in-human trial of vafidemstat in healthy young and older adult volunteers. A total of 110 volunteers participated: 87 were treated with vafidemstat and 23 with placebo. Objectives: The study aimed to determine the safety and tolerability of vafidemstat, to characterize its pharmacokinetic and pharmacodynamic profiles, to assess its central nervous system (CNS) exposure, and to acquire the necessary data to select the appropriate doses for long-term treatment of patients with CNS disease in phase II trials. Methods: This single-center, randomized, double-blind, placebo-controlled phase I trial included a single and 5-day repeated dose-escalation and open-label CNS penetration substudy. Primary outcomes were safety and tolerability; secondary outcomes included analysis of the pharmacokinetics and pharmacodynamics, including chemoprobe-based immune analysis of KDM1A target engagement (TE) in peripheral blood mononuclear cells (PBMCs) and platelet monoamine oxidase B (MAOB) inhibition. CNS and cognitive function were also evaluated. Results: No severe adverse events (AEs) were reported in the dose-escalation stage. AEs were reported at all dose levels; none were dose dependent, and no significant differences were observed between active treatment and placebo. Biochemistry, urinalysis, vital signs, electrocardiogram, and hematology did not change significantly with dose escalation, with the exception of a transient reduction of platelet counts in an extra dose level incorporated for that purpose. Vafidemstat exhibits rapid oral absorption, approximate dose-proportional exposures, and moderate systemic accumulation after 5 days of treatment. The cerebrospinal fluid-to-plasma unbound ratio demonstrated CNS penetration. Vafidemstat bound KDM1A in PBMCs in a dose-dependent manner. No MAOB inhibition was detected. Vafidemstat did not affect the CNS or cognitive function. Conclusions: Vafidemstat displayed good safety and tolerability. This phase I trial confirmed KDM1A TE and CNS penetration and permitted characterization of platelet dynamics and selection of phase IIa doses. Trial registration: EUDRACT No. 2015-003721-33, filed 30 October 2015.
MeSH term(s)	Area Under Curve ; Central Nervous System/drug effects ; Double-Blind Method ; Female ; Histone Demethylases/antagonists & inhibitors ; Humans ; Leukocytes, Mononuclear/drug effects ; Leukocytes, Mononuclear/metabolism ; Male ; Monoamine Oxidase Inhibitors/pharmacokinetics ; Monoamine Oxidase Inhibitors/pharmacology ; Oxadiazoles/pharmacokinetics ; Oxadiazoles/therapeutic use
Chemical Substances	Monoamine Oxidase Inhibitors ; Oxadiazoles ; Histone Demethylases (EC 1.14.11.-) ; KDM1A protein, human (EC 1.5.-) ; vafidemstat (LZ82JLT4UP)
Language	English
Publishing date	2021-03-23
Publishing country	New Zealand
Document type	Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	1203800-3
ISSN	1179-1934 ; 1172-7047
ISSN (online)	1179-1934
ISSN	1172-7047
DOI	10.1007/s40263-021-00797-x
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Zs.A 4083: Show issues

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Article ; Online: First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia.

Salamero, Olga / Montesinos, Pau / Willekens, Christophe / Pérez-Simón, José Antonio / Pigneux, Arnaud / Récher, Christian / Popat, Rakesh / Carpio, Cecilia / Molinero, César / Mascaró, Cristina / Vila, Joaquim / Arévalo, M Isabel / Maes, Tamara / Buesa, Carlos / Bosch, Francesc / Somervaille, Tim C P

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

2020 Volume 38, Issue 36, Page(s) 4260–4273

Abstract: Purpose: Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with ... ...

Abstract	Purpose: Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Methods: This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor. Results: Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m Conclusion: Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36).
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Female ; Histone Demethylases/antagonists & inhibitors ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Male ; Middle Aged ; Recurrence
Chemical Substances	Enzyme Inhibitors ; Histone Demethylases (EC 1.14.11.-)
Language	English
Publishing date	2020-10-14
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604914-x
ISSN	1527-7755 ; 0732-183X
ISSN (online)	1527-7755
ISSN	0732-183X
DOI	10.1200/JCO.19.03250
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Article ; Online: KDM1 histone lysine demethylases as targets for treatments of oncological and neurodegenerative disease.

Maes, Tamara / Mascaró, Cristina / Ortega, Alberto / Lunardi, Serena / Ciceri, Filippo / Somervaille, Tim C P / Buesa, Carlos

Epigenomics

2015 Volume 7, Issue 4, Page(s) 609–626

Abstract: Histone methylation and demethylation are important processes associated with the regulation of gene transcription, and alterations in histone methylation status have been linked to a large number of human diseases. Initially thought to be an ... ...

Abstract	Histone methylation and demethylation are important processes associated with the regulation of gene transcription, and alterations in histone methylation status have been linked to a large number of human diseases. Initially thought to be an irreversible process, histone methylation is now known to be reversed by two families of proteins containing over 30 members that act to remove methyl groups from specific lysine residues present in the tails of histone H3 and histone H4. A rapidly growing number of reports have implicated the FAD-dependent lysine specific demethylase (KDM1) family in cancer, and several small-molecule inhibitors are in development for the treatment of cancer. An additional role has emerged for KDM1 in brain function, offering additional opportunities for the development of novel therapeutic strategies in neurodegenerative disease. A decade after the identification of KDM1A as a histone demethylase, the first selective inhibitors have now reached the clinic.
MeSH term(s)	Amino Acid Sequence ; Animals ; Epigenesis, Genetic ; Genetic Therapy ; Histone Demethylases/chemistry ; Histone Demethylases/genetics ; Histone Demethylases/metabolism ; Humans ; Molecular Sequence Data ; Neoplasms/genetics ; Neoplasms/therapy ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/therapy
Chemical Substances	Histone Demethylases (EC 1.14.11.-) ; KDM1A protein, human (EC 1.5.-)
Language	English
Publishing date	2015-06-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2537199-X
ISSN	1750-192X ; 1750-1911
ISSN (online)	1750-192X
ISSN	1750-1911
DOI	10.2217/epi.15.9
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Article: Neuron navigator: a human gene family with homology to unc-53, a cell guidance gene from Caenorhabditis elegans.

Maes, Tamara / Barceló, Anna / Buesa, Carlos

Genomics

2002 Volume 80, Issue 1, Page(s) 21–30

Abstract: We have cloned the gene neuron navigator-1 (NAV1), a human homolog of unc-53, a gene involved in axon guidance in Caenorhabditis elegans. Duplications during evolution gave rise to three human homologs located on chromosomes 1q32.1, 11p15.1, and 12q21.1. ...

Abstract	We have cloned the gene neuron navigator-1 (NAV1), a human homolog of unc-53, a gene involved in axon guidance in Caenorhabditis elegans. Duplications during evolution gave rise to three human homologs located on chromosomes 1q32.1, 11p15.1, and 12q21.1. NAV1 and NAV2 are expressed in the developing brain. NAV1, NAV2, and NAV3 expression is detected in adult heart, kidney, and brain, respectively. NAV1 encodes a protein lacking, in the aminoterminal part, a CH domain present in the other NAV genes. The first exon of NAV1 arose through an ancient internal duplication of sequences that also gave rise to exon 8 of NAV3 and exon 7 of NAV2. A detailed study of the NAV environment on the different chromosomes reveals incomplete micro-syntheny between the three regions. Through analysis of the phylogenetic relationships for three different gene families in the NAV environment, we reconstructed part of the events that formed these regions.
MeSH term(s)	Alternative Splicing ; Amino Acid Sequence ; Animals ; Blotting, Northern ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans Proteins/genetics ; Drosophila/genetics ; Evolution, Molecular ; Humans ; Microfilament Proteins/genetics ; Microtubule-Associated Proteins ; Molecular Sequence Data ; Multigene Family ; Nerve Growth Factors/genetics ; Nerve Tissue Proteins/genetics ; Organ Specificity ; Phylogeny ; Sequence Alignment ; Synteny
Chemical Substances	Caenorhabditis elegans Proteins ; Microfilament Proteins ; Microtubule-Associated Proteins ; NAV1 protein, human ; Nerve Growth Factors ; Nerve Tissue Proteins ; UNC-53 protein, C elegans ; NAV2 protein, human (EC 5.99.-)
Language	English
Publishing date	2002-06-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	356334-0
ISSN	1089-8646 ; 0888-7543
ISSN (online)	1089-8646
ISSN	0888-7543
DOI	10.1006/geno.2002.6799
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Zs.A 2367: Show issues

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Article: DNA chip technology in brain banks: confronting a degrading world.

Buesa, Carlos / Maes, Tamara / Subirada, Francesca / Barrachina, Marta / Ferrer, Isidro

Journal of neuropathology and experimental neurology

2004 Volume 63, Issue 10, Page(s) 1003–1014

Abstract: DNA microarray technology is based on the principle of hybridization between 2 complementary strands of nucleic acids, one being fixed into a solid membrane, the other being the sample to analyze. This has resulted in a very powerful method to examine ... ...

Abstract	DNA microarray technology is based on the principle of hybridization between 2 complementary strands of nucleic acids, one being fixed into a solid membrane, the other being the sample to analyze. This has resulted in a very powerful method to examine differential gene expression between samples, and has been widely used in the study of tumors. The application of DNA microarray technology to the study of the nervous system has to consider several properties of the nervous tissue: composition of various neuronal types, as well as astrocytes, oligodendrocytes, and microglia; regional and area differences; developmental and age-dependent variations; and functional and pathological status. Moreover, human samples are usually obtained postmortem following variable agonal periods and postmortem delays between death and tissue preservation, which are accompanied by variable RNA degradation. Yet human postmortem nervous tissue stored in brain banks offers a unique opportunity to facilitate material for the study of diseases of the nervous system and to gain direct understanding on the mechanisms of disease. This review analyzes the application of DNA microarray technology to current practice using brain-banked tissues in order to recognize and minimize sub-optimal processing of brain samples and to correct pitfalls due to inadequate procedures. Also discussed are RNA preservation and RNA degradation effects on expression pattern assessments, analysis of individual versus pooled samples, array normalization, types of DNA chip platforms, whole genomic analysis versus specialized chips, and microgenomics. Minimizing RNA degradation and improving detection of resistant RNA in postmortem brain has been considered in detail in order to improve the efficiency and reliability of DNA microarray technology employed in the study of human postmortem nervous tissue.
MeSH term(s)	Animals ; Brain/metabolism ; Cadaver ; Genomics ; Humans ; Hypoxia/metabolism ; Neurobiology ; Oligonucleotide Array Sequence Analysis ; RNA/metabolism ; Tissue Banks
Chemical Substances	RNA (63231-63-0)
Language	English
Publishing date	2004-10-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	3088-0
ISSN	1554-6578 ; 0022-3069
ISSN (online)	1554-6578
ISSN	0022-3069
DOI	10.1093/jnen/63.10.1003
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Article ; Online: ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia.

Cancer cell

2018 Volume 33, Issue 3, Page(s) 495–511.e12

Abstract: The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and ...

Abstract	The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors.
MeSH term(s)	Animals ; Apoptosis/drug effects ; Cell Differentiation/drug effects ; Cell Line, Tumor/metabolism ; Disease Models, Animal ; Histone Demethylases/antagonists & inhibitors ; Histone Demethylases/drug effects ; Histone Demethylases/genetics ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Mice ; Stem Cells/drug effects ; Stem Cells/metabolism
Chemical Substances	Histone Demethylases (EC 1.14.11.-) ; KDM1A protein, human (EC 1.5.-)
Language	English
Publishing date	2018-03-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2018.02.002
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Article: Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies.

Barrachina, Marta / Castaño, Esther / Dalfó, Esther / Maes, Tamara / Buesa, Carlos / Ferrer, Isidro

Neurobiology of disease

2005 Volume 22, Issue 2, Page(s) 265–273

Abstract: Parkinson disease (PD) and dementia with Lewy bodies (DLB) are characterized by the accumulation of abnormal alpha-synuclein and ubiquitin in protein aggregates conforming Lewy bodies and Lewy neurites. Ubiquitin C-terminal hydrolase-1 (UCHL-1) ... ...

Abstract	Parkinson disease (PD) and dementia with Lewy bodies (DLB) are characterized by the accumulation of abnormal alpha-synuclein and ubiquitin in protein aggregates conforming Lewy bodies and Lewy neurites. Ubiquitin C-terminal hydrolase-1 (UCHL-1) disassembles polyubiquitin chains to increase the availability of free monomeric ubiquitin to the ubiquitin proteasome system (UPS) thus favoring protein degradation. Since mutations in the UCHL-1 gene, reducing UPS activity by 50%, have been reported in autosomal dominant PD, and UCHL-1 inhibition results in the formation of alpha-synuclein aggregates in mesencephalic cultured neurons, the present study was initiated to test UCHL-1 mRNA and protein levels in post-mortem frontal cortex (area 8) of PD and DLB cases, compared with age-matched controls. TaqMan PCR assays, and Western blots demonstrated down-regulation of UCHL-1 mRNA and UCHL-1 protein in the cerebral cortex in DLB (either in pure forms, not associated with Alzheimer disease: AD, and in common forms, with accompanying AD changes), but not in PD, when compared with age-matched controls. Interestingly, UCHL-1 mRNA and protein expressions were reduced in the medulla oblongata in the same PD cases. Moreover, UCHL-1 protein was decreased in the substantia nigra in cases with Lewy body pathology. UCHL-1 down-regulation was not associated with reduced protein levels of several proteasomal subunits, including 20SX, 20SY, 19S and 11Salpha. Yet UCHL-3 expression was reduced in the cerebral cortex of PD and DLB patients. Together, these observations show reduced UCHL-1 expression as a contributory factor in the abnormal protein aggregation in DLB, and points UCHL-1 as a putative therapeutic target in the treatment of DLB.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/enzymology ; Alzheimer Disease/genetics ; Alzheimer Disease/physiopathology ; Brain/enzymology ; Brain/pathology ; Brain/physiopathology ; Cerebral Cortex/enzymology ; Cerebral Cortex/pathology ; Cerebral Cortex/physiopathology ; Down-Regulation/physiology ; Female ; Humans ; Lewy Bodies/enzymology ; Lewy Bodies/genetics ; Lewy Body Disease/enzymology ; Lewy Body Disease/genetics ; Lewy Body Disease/physiopathology ; Male ; Medulla Oblongata/enzymology ; Medulla Oblongata/pathology ; Medulla Oblongata/physiopathology ; Middle Aged ; Neurons/enzymology ; Neurons/pathology ; Parkinson Disease/enzymology ; Parkinson Disease/genetics ; Parkinson Disease/physiopathology ; Proteasome Endopeptidase Complex/genetics ; Proteasome Endopeptidase Complex/metabolism ; Protein Subunits/genetics ; Protein Subunits/metabolism ; RNA, Messenger/metabolism ; Signal Transduction/physiology ; Substantia Nigra/enzymology ; Substantia Nigra/pathology ; Substantia Nigra/physiopathology ; Ubiquitin/metabolism ; Ubiquitin Thiolesterase/genetics ; Ubiquitin Thiolesterase/metabolism
Chemical Substances	Protein Subunits ; RNA, Messenger ; UCHL1 protein, human ; Ubiquitin ; Ubiquitin Thiolesterase (EC 3.4.19.12) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2005-12-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2005.11.005
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Zs.A 4444: Show issues

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Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

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