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Molecular Neurodegeneration

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https://www.readbyqxmd.com/read/30092810/immunotherapy-targeting-toll-like-receptor-2-alleviates-neurodegeneration-in-models-of-synucleinopathy-by-modulating-%C3%AE-synuclein-transmission-and-neuroinflammation
#1
Changyoun Kim, Brian Spencer, Edward Rockenstein, Hodaka Yamakado, Michael Mante, Anthony Adame, Jerel Adam Fields, Deborah Masliah, Michiyo Iba, He-Jin Lee, Robert A Rissman, Seung-Jae Lee, Eliezer Masliah
BACKGROUND: Synucleinopathies of the aging population are an heterogeneous group of neurological disorders that includes Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and are characterized by the progressive accumulation of α-synuclein in neuronal and glial cells. Toll-like receptor 2 (TLR2), a pattern recognition immune receptor, has been implicated in the pathogenesis of synucleinopathies because TLR2 is elevated in the brains of patients with PD and TLR2 is a mediator of the neurotoxic and pro-inflammatory effects of extracellular α-synuclein aggregates...
August 9, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/30092791/counteracting-roles-of-mhci-and-cd8-t-cells-in-the-peripheral-and-central-nervous-system-of-als-sod1-g93a-mice
#2
Giovanni Nardo, Maria Chiara Trolese, Mattia Verderio, Alessandro Mariani, Massimiliano de Paola, Nilo Riva, Giorgia Dina, Nicolò Panini, Eugenio Erba, Angelo Quattrini, Caterina Bendotti
BACKGROUND: The major histocompatibility complex I (MHCI) is a key molecule for the interaction of mononucleated cells with CD8+ T lymphocytes. We previously showed that MHCI is upregulated in the spinal cord microglia and motor axons of transgenic SOD1G93A mice. METHODS: To assess the role of MHCI in the disease, we examined transgenic SOD1G93A mice crossbred with β2 microglobulin-deficient mice, which express little if any MHCI on the cell surface and are defective for CD8+ T cells...
August 9, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/30089514/joint-genome-wide-association-study-of-progressive-supranuclear-palsy-identifies-novel-susceptibility-loci-and-genetic-correlation-to-neurodegenerative-diseases
#3
Jason A Chen, Zhongbo Chen, Hyejung Won, Alden Y Huang, Jennifer K Lowe, Kevin Wojta, Jennifer S Yokoyama, Gilbert Bensimon, P Nigel Leigh, Christine Payan, Aleksey Shatunov, Ashley R Jones, Cathryn M Lewis, Panagiotis Deloukas, Philippe Amouyel, Christophe Tzourio, Jean-Francois Dartigues, Albert Ludolph, Adam L Boxer, Jeff M Bronstein, Ammar Al-Chalabi, Daniel H Geschwind, Giovanni Coppola
BACKGROUND: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease for which the genetic contribution is incompletely understood. METHODS: We conducted a joint analysis of 5,523,934 imputed SNPs in two newly-genotyped progressive supranuclear palsy cohorts, primarily derived from two clinical trials (Allon davunetide and NNIPPS riluzole trials in PSP) and a previously published genome-wide association study (GWAS), in total comprising 1646 cases and 10,662 controls of European ancestry...
August 8, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/30071902/a-new-hypothesis-for-parkinson-s-disease-pathogenesis-gtpase-p38-mapk-signaling-and-autophagy-as-convergence-points-of-etiology-and-genomics
#4
REVIEW
Julia Obergasteiger, Giulia Frapporti, Peter P Pramstaller, Andrew A Hicks, Mattia Volta
The combination of genetics and genomics in Parkinson´s disease has recently begun to unveil molecular mechanisms possibly underlying disease onset and progression. In particular, catabolic processes such as autophagy have been increasingly gaining relevance as post-mortem evidence and experimental models suggested a participation in neurodegeneration and alpha-synuclein Lewy body pathology. In addition, familial Parkinson´s disease linked to LRRK2 and alpha-synuclein provided stronger correlation between etiology and alterations in autophagy...
August 2, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/30068350/transcriptional-profiling-of-herv-k-hml-2-in-amyotrophic-lateral-sclerosis-and-potential-implications-for-expression-of-hml-2-proteins
#5
Jens Mayer, Christian Harz, Laura Sanchez, Gavin C Pereira, Esther Maldener, Sara R Heras, Lyle W Ostrow, John Ravits, Ranjan Batra, Eckart Meese, Jose Luis García-Pérez, John L Goodier
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. About 90% of ALS cases are without a known genetic cause. The human endogenous retrovirus multi-copy HERV-K(HML-2) group was recently reported to potentially contribute to neurodegeneration and disease pathogenesis in ALS because of transcriptional upregulation and toxic effects of HML-2 Envelope (Env) protein. Env and other proteins are encoded by some transcriptionally active HML-2 loci. However, more detailed information is required regarding which HML-2 loci are transcribed in ALS, which of their proteins are expressed, and differences between the disease and non-disease states...
August 2, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/30041668/polygenic-analysis-of-inflammatory-disease-variants-and-effects-on-microglia-in-the-aging-brain
#6
Daniel Felsky, Ellis Patrick, Julie A Schneider, Sara Mostafavi, Chris Gaiteri, Nikolaos Patsopoulos, David A Bennett, Philip L De Jager
BACKGROUND: The role of the innate immune system in Alzheimer's disease (AD) and neurodegenerative disease susceptibility has recently been highlighted in genetic studies. However, we do not know whether risk for inflammatory disease predisposes unaffected individuals to late-life cognitive deficits or AD-related neuropathology. We investigated whether genetic risk scores for seven immune diseases and central nervous system traits were related to cognitive decline (nmax  = 1601), classical AD neuropathology (nmax  = 985), or microglial density (nmax  = 184)...
July 24, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29986742/replication-of-progressive-supranuclear-palsy-genome-wide-association-study-identifies-slco1a2-and-dusp10-as-new-susceptibility-loci
#7
Monica Y Sanchez-Contreras, Naomi Kouri, Casey N Cook, Daniel J Serie, Michael G Heckman, NiCole A Finch, Richard J Caselli, Ryan J Uitti, Zbigniew K Wszolek, Neill Graff-Radford, Leonard Petrucelli, Li-San Wang, Gerard D Schellenberg, Dennis W Dickson, Rosa Rademakers, Owen A Ross
BACKGROUND: Progressive supranuclear palsy (PSP) is a parkinsonian neurodegenerative tauopathy affecting brain regions involved in motor function, including the basal ganglia, diencephalon and brainstem. While PSP is largely considered to be a sporadic disorder, cases with suspected familial inheritance have been identified and the common MAPT H1haplotype is a major genetic risk factor. Due to the relatively low prevalence of PSP, large sample sizes can be difficult to achieve, and this has limited the ability to detect true genetic risk factors at the genome-wide statistical threshold for significance in GWAS data...
July 9, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29980238/clinical-spectrum-and-genetic-landscape-for-hereditary-spastic-paraplegias-in-china
#8
En-Lin Dong, Chong Wang, Shuang Wu, Ying-Qian Lu, Xiao-Hong Lin, Hui-Zhen Su, Miao Zhao, Jin He, Li-Xiang Ma, Ning Wang, Wan-Jin Chen, Xiang Lin
BACKGROUND: Hereditary spastic paraplegias (HSP) is a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts. To date, more than 78 HSP loci have been mapped to cause HSP. However, both the clinical and mutational spectrum of Chinese patients with HSP remained unclear. In this study, we aim to perform a comprehensive analysis of clinical phenotypes and genetic distributions in a large cohort of Chinese HSP patients, and to elucidate the primary pathogenesis in this population...
July 6, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29970152/tmem106b-haplotypes-have-distinct-gene-expression-patterns-in-aged-brain
#9
Yingxue Ren, Marka van Blitterswijk, Mariet Allen, Minerva M Carrasquillo, Joseph S Reddy, Xue Wang, Thomas G Beach, Dennis W Dickson, Nilüfer Ertekin-Taner, Yan W Asmann, Rosa Rademakers
BACKGROUND: Single nucleotide polymorphisms (SNPs) inherited as one of two common haplotypes at the transmembrane protein 106B (TMEM106B) locus are associated with the risk of multiple neurodegenerative diseases, including frontotemporal lobar degeneration with pathological inclusions of TDP-43. Among the associated variants, rs3173615 (encoding p.T185S) is the only coding variant; however, non-coding variants may also contribute to disease risk. It has been reported that the risk haplotype is associated with higher levels of TMEM106B and increased levels of TMEM106B cause cytotoxicity; however, the precise mechanism through which TMEM106B haplotypes contribute to neurodegeneration is unclear...
July 3, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29954413/quantitative-proteomics-of-acutely-isolated-mouse-microglia-identifies-novel-immune-alzheimer-s-disease-related-proteins
#10
Srikant Rangaraju, Eric B Dammer, Syed Ali Raza, Tianwen Gao, Hailian Xiao, Ranjita Betarbet, Duc M Duong, James A Webster, Chadwick M Hales, James J Lah, Allan I Levey, Nicholas T Seyfried
BACKGROUND: Microglia are innate immune cells of the brain that perform phagocytic and inflammatory functions in disease conditions. Transcriptomic studies of acutely-isolated microglia have provided novel insights into their molecular and functional diversity in homeostatic and neurodegenerative disease states. State-of-the-art mass spectrometry methods can comprehensively characterize proteomic alterations in microglia in neurodegenerative disorders, potentially providing novel functionally relevant molecular insights that are not provided by transcriptomics...
June 28, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29945658/ipsc-derived-familial-alzheimer-s-psen2-n141i-cholinergic-neurons-exhibit-mutation-dependent-molecular-pathology-corrected-by-insulin-signaling
#11
Cesar L Moreno, Lucio Della Guardia, Valeria Shnyder, Maitane Ortiz-Virumbrales, Ilya Kruglikov, Bin Zhang, Eric E Schadt, Rudolph E Tanzi, Scott Noggle, Christoph Buettner, Sam Gandy
BACKGROUND: Type 2 diabetes (T2D) is a recognized risk factor for the development of cognitive impairment (CI) and/or dementia, although the exact nature of the molecular pathology of T2D-associated CI remains obscure. One link between T2D and CI might involve decreased insulin signaling in brain and/or neurons in either animal or postmortem human brains as has been reported as a feature of Alzheimer's disease (AD). Here we asked if neuronal insulin resistance is a cell autonomous phenomenon in a familial form of AD...
June 26, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29929540/transcriptional-profiling-and-biomarker-identification-reveal-tissue-specific-effects-of-expanded-ataxin-3-in-a-spinocerebellar-ataxia-type-3-mouse-model
#12
Lodewijk J A Toonen, Maurice Overzier, Melvin M Evers, Leticia G Leon, Sander A J van der Zeeuw, Hailiang Mei, Szymon M Kielbasa, Jelle J Goeman, Kristina M Hettne, Olafur Th Magnusson, Marion Poirel, Alexandre Seyer, Peter A C 't Hoen, Willeke M C van Roon-Mom
BACKGROUND: Spinocerebellar ataxia type 3 (SCA3) is a progressive neurodegenerative disorder caused by expansion of the polyglutamine repeat in the ataxin-3 protein. Expression of mutant ataxin-3 is known to result in transcriptional dysregulation, which can contribute to the cellular toxicity and neurodegeneration. Since the exact causative mechanisms underlying this process have not been fully elucidated, gene expression analyses in brains of transgenic SCA3 mouse models may provide useful insights...
June 22, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29929528/partial-tmem106b-reduction-does-not-correct-abnormalities-due-to-progranulin-haploinsufficiency
#13
Andrew E Arrant, Alexandra M Nicholson, Xiaolai Zhou, Rosa Rademakers, Erik D Roberson
BACKGROUND: Loss of function mutations in progranulin (GRN) are a major cause of frontotemporal dementia (FTD). Progranulin is a secreted glycoprotein that localizes to lysosomes and is critical for proper lysosomal function. Heterozygous GRN mutation carriers develop FTD with TDP-43 pathology and exhibit signs of lysosomal dysfunction in the brain, with increased levels of lysosomal proteins and lipofuscin accumulation. Homozygous GRN mutation carriers develop neuronal ceroid lipofuscinosis (NCL), an earlier-onset lysosomal storage disorder caused by severe lysosomal dysfunction...
June 22, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29859124/protective-paraspeckle-hyper-assembly-downstream-of-tdp-43-loss-of-function-in-amyotrophic-lateral-sclerosis
#14
Tatyana A Shelkovnikova, Michail S Kukharsky, Haiyan An, Pasquale Dimasi, Svetlana Alexeeva, Osman Shabir, Paul R Heath, Vladimir L Buchman
BACKGROUND: Paraspeckles are subnuclear bodies assembled on a long non-coding RNA (lncRNA) NEAT1. Their enhanced formation in spinal neurons of sporadic amyotrophic lateral sclerosis (ALS) patients has been reported but underlying mechanisms are unknown. The majority of ALS cases are characterized by TDP-43 proteinopathy. In current study we aimed to establish whether and how TDP-43 pathology may augment paraspeckle assembly. METHODS: Paraspeckle formation in human samples was analysed by RNA-FISH and laser capture microdissection followed by qRT-PCR...
June 1, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29859094/the-trem2-r47h-variant-confers-loss-of-function-like-phenotypes-in-alzheimer-s-disease
#15
Paul J Cheng-Hathaway, Erin G Reed-Geaghan, Taylor R Jay, Brad T Casali, Shane M Bemiller, Shweta S Puntambekar, Victoria E von Saucken, Roxanne Y Williams, J Colleen Karlo, Miguel Moutinho, Guixiang Xu, Richard M Ransohoff, Bruce T Lamb, Gary E Landreth
BACKGROUND: The R47H variant of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) confers greatly increased risk for Alzheimer's disease (AD), reflective of a central role for myeloid cells in neurodegeneration. Understanding how this variant confers AD risk promises to provide important insights into how myeloid cells contribute to AD pathogenesis and progression. METHODS: In order to investigate this mechanism, CRISPR/Cas9 was used to generate a mouse model of AD harboring one copy of the single nucleotide polymorphism (SNP) encoding the R47H variant in murine Trem2...
June 1, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29793507/targeting-energy-metabolism-via-the-mitochondrial-pyruvate-carrier-as-a-novel-approach-to-attenuate-neurodegeneration
#16
REVIEW
Emmanuel Quansah, Wouter Peelaerts, J William Langston, David K Simon, Jerry Colca, Patrik Brundin
Several molecular pathways are currently being targeted in attempts to develop disease-modifying therapies to slow down neurodegeneration in Parkinson's disease. Failure of cellular energy metabolism has long been implicated in sporadic Parkinson's disease and recent research on rare inherited forms of Parkinson's disease have added further weight to the importance of energy metabolism in the disease pathogenesis. There exists a new class of anti-diabetic insulin sensitizers in development that inhibit the mitochondrial pyruvate carrier (MPC), a protein which mediates the import of pyruvate across the inner membrane of mitochondria...
May 24, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29788997/2d-versus-3d-human-induced-pluripotent-stem-cell-derived-cultures-for-neurodegenerative-disease-modelling
#17
REVIEW
Eduarda G Z Centeno, Helena Cimarosti, Angela Bithell
Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), affect millions of people every year and so far, there are no therapeutic cures available. Even though animal and histological models have been of great aid in understanding disease mechanisms and identifying possible therapeutic strategies, in order to find disease-modifying solutions there is still a critical need for systems that can provide more predictive and physiologically relevant results...
May 22, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29784049/identification-and-therapeutic-modulation-of-a-pro-inflammatory-subset-of-disease-associated-microglia-in-alzheimer-s-disease
#18
Srikant Rangaraju, Eric B Dammer, Syed Ali Raza, Priyadharshini Rathakrishnan, Hailian Xiao, Tianwen Gao, Duc M Duong, Michael W Pennington, James J Lah, Nicholas T Seyfried, Allan I Levey
BACKGROUND: Disease-associated-microglia (DAM) represent transcriptionally-distinct and neurodegeneration-specific microglial profiles with unclear significance in Alzheimer's disease (AD). An understanding of heterogeneity within DAM and their key regulators may guide pre-clinical experimentation and drug discovery. METHODS: Weighted co-expression network analysis (WGCNA) was applied to existing microglial transcriptomic datasets from neuroinflammatory and neurodegenerative disease mouse models to identify modules of highly co-expressed genes...
May 21, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29783994/large-scale-transcriptomic-analysis-reveals-that-pridopidine-reverses-aberrant-gene-expression-and-activates-neuroprotective-pathways-in-the-yac128-hd-mouse
#19
Rebecca Kusko, Jennifer Dreymann, Jermaine Ross, Yoonjeong Cha, Renan Escalante-Chong, Marta Garcia-Miralles, Liang Juin Tan, Michael E Burczynski, Ben Zeskind, Daphna Laifenfeld, Mahmoud Pouladi, Michal Geva, Iris Grossman, Michael R Hayden
BACKGROUND: Huntington Disease (HD) is an incurable autosomal dominant neurodegenerative disorder driven by an expansion repeat giving rise to the mutant huntingtin protein (mHtt), which is known to disrupt a multitude of transcriptional pathways. Pridopidine, a small molecule in development for treatment of HD, has been shown to improve motor symptoms in HD patients. In HD animal models, pridopidine exerts neuroprotective effects and improves behavioral and motor functions. Pridopidine binds primarily to the sigma-1 receptor, (IC50 ~ 100 nM), which mediates its neuroprotective properties, such as rescue of spine density and aberrant calcium signaling in HD neuronal cultures...
May 21, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29783988/tolerogenic-bone-marrow-derived-dendritic-cells-induce-neuroprotective-regulatory-t-cells-in-a-model-of-parkinson-s-disease
#20
Charles R Schutt, Howard E Gendelman, R Lee Mosley
BACKGROUND: Administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) increases regulatory T cell (Treg) number and function with control of neuroinflammation and neuronal protection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease (PD). Recently, we demonstrated in an early phase 1 clinical trial that GM-CSF also improves motor skills in PD patients. However, the mechanisms of Treg induction and its effects on neuroprotective responses remain unknown...
May 21, 2018: Molecular Neurodegeneration
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