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TREM2 Parkinson

Gail Chan, Charles C White, Phoebe A Winn, Maria Cimpean, Joseph M Replogle, Laura R Glick, Nicole E Cuerdon, Katie J Ryan, Keith A Johnson, Julie A Schneider, David A Bennett, Lori B Chibnik, Reisa A Sperling, Philip L De Jager, Elizabeth M Bradshaw
OBJECTIVE: Given evidence from genetic studies, we hypothesized that there may be a shared component to the role of myeloid function in Parkinson and Alzheimer disease (PD and AD) and assessed whether PD susceptibility variants influenced protein expression of well-established AD-associated myeloid genes in human monocytes. METHODS: We repurposed data in which AD-related myeloid proteins CD33, TREM1, TREM2, TREML2, TYROBP, and PTK2B were measured by flow cytometry in monocytes from 176 participants of the PhenoGenetic Project (PGP) and Harvard Aging Brain Study...
August 2016: Neurology. Genetics
Ronald L Walton, Alexandra I Soto-Ortolaza, Melissa E Murray, Oswaldo Lorenzo-Betancor, Kotaro Ogaki, Michael G Heckman, Sruti Rayaprolu, Rosa Rademakers, Nilüfer Ertekin-Taner, Ryan J Uitti, Jay A van Gerpen, Zbigniew K Wszolek, Glenn E Smith, Kejal Kantarci, Val J Lowe, Joseph E Parisi, David T Jones, Rodolfo Savica, Jonathan Graff-Radford, David S Knopman, Ronald C Petersen, Neill R Graff-Radford, Tanis J Ferman, Dennis W Dickson, Bradley F Boeve, Owen A Ross, Catherine Labbé
Dementia with Lewy bodies (DLB) is the second leading cause of neurodegenerative dementia in the elderly and is clinically characterized by the presence of cognitive decline, parkinsonism, REM sleep behavior disorder, and visual hallucinations.(1,2) At autopsy, α-synuclein-positive Lewy-related pathology is observed throughout the brain. Concomitant Alzheimer disease-related pathology including amyloid plaques and, to a lesser degree, neurofibrillary tangles are often present.(2) The clinical characteristics of DLB share overlapping features with Alzheimer disease dementia (AD) and Parkinson disease (PD)...
August 2016: Neurology. Genetics
José Fidel Baizabal-Carvallo, Joseph Jankovic
Frontotemporal dementia (FTD) refers to a group of clinically and genetically heterogeneous neurodegenerative disorders that are a common cause of adult-onset behavioural and cognitive impairment. FTD often presents in combination with various hyperkinetic or hypokinetic movement disorders, and evidence suggests that various genetic mutations underlie these different presentations. Here, we review the known syndromatic-genetic correlations in FTD. Although no direct genotype-phenotype correlations have been identified, mutations in multiple genes have been associated with various presentations...
March 2016: Nature Reviews. Neurology
Yuka Atagi, Chia-Chen Liu, Meghan M Painter, Xiao-Fen Chen, Christophe Verbeeck, Honghua Zheng, Xia Li, Rosa Rademakers, Silvia S Kang, Huaxi Xu, Steven Younkin, Pritam Das, John D Fryer, Guojun Bu
Several heterozygous missense mutations in the triggering receptor expressed on myeloid cells 2 (TREM2) have recently been linked to risk for a number of neurological disorders including Alzheimer disease (AD), Parkinson disease, and frontotemporal dementia. These discoveries have re-ignited interest in the role of neuroinflammation in the pathogenesis of neurodegenerative diseases. TREM2 is highly expressed in microglia, the resident immune cells of the central nervous system. Along with its adaptor protein, DAP12, TREM2 regulates inflammatory cytokine release and phagocytosis of apoptotic neurons...
October 23, 2015: Journal of Biological Chemistry
Guiyou Liu, Yongquan Liu, Qinghua Jiang, Yongshuai Jiang, Rennan Feng, Liangcai Zhang, Zugen Chen, Keshen Li, Jiafeng Liu
A rare TREM2 missense mutation (rs75932628-T) was reported to confer a significant Alzheimer's disease (AD) risk. A recent study indicated no evidence of the involvement of this variant in Parkinson's disease (PD). Here, we used the genetic and expression data to reinvestigate the potential association between TREM2 and PD susceptibility. In stage 1, using 10 independent studies (N = 89,157; 8787 cases and 80,370 controls), we conducted a subgroup meta-analysis. We identified a significant association between rs75932628 and PD (P = 3...
September 2016: Molecular Neurobiology
Olena Korvatska, James B Leverenz, Suman Jayadev, Pamela McMillan, Irina Kurtz, Xindi Guo, Malia Rumbaugh, Mark Matsushita, Santhosh Girirajan, Michael O Dorschner, Kostantin Kiianitsa, Chang-En Yu, Zoran Brkanac, Gwenn A Garden, Wendy H Raskind, Thomas D Bird
IMPORTANCE: The R47H variant in the triggering receptor expressed on myeloid cells 2 gene (TREM2), a modulator of the immune response of microglia, is a strong genetic risk factor for Alzheimer disease (AD) and possibly other neurodegenerative disorders. OBJECTIVE: To investigate a large family with late-onset AD (LOAD), in which R47H cosegregated with 75% of cases. DESIGN, SETTING, AND PARTICIPANTS: This study includes genetic and pathologic studies of families with LOAD from 1985 to 2014...
August 2015: JAMA Neurology
Yongping Chen, Xueping Chen, Xiaoyan Guo, Wei Song, Bei Cao, Qianqian Wei, Ruwei Ou, Bi Zhao, Hui-Fang Shang
Although rs75932628 in triggering receptor expressed on myeloid cells 2 (TREM2) was shown to increase the risk for Alzheimer's disease, there is no agreement on the association between this variant and the risk for Parkinson's disease (PD). Considering the overlapping of clinical manifestation and pathologic characteristics of PD and multiple system atrophy (MSA), we conducted a large-sample study to investigate the associations between this variant and these two neurodegenerative diseases in a Chinese population...
October 2015: Neurological Sciences
Christina M Lill, Aina Rengmark, Lasse Pihlstrøm, Isabella Fogh, Aleksey Shatunov, Patrick M Sleiman, Li-San Wang, Tian Liu, Christina F Lassen, Esther Meissner, Panos Alexopoulos, Andrea Calvo, Adriano Chio, Nil Dizdar, Frank Faltraco, Lars Forsgren, Julia Kirchheiner, Alexander Kurz, Jan P Larsen, Maria Liebsch, Jan Linder, Karen E Morrison, Hans Nissbrandt, Markus Otto, Jens Pahnke, Amanda Partch, Gabriella Restagno, Dan Rujescu, Cathrin Schnack, Christopher E Shaw, Pamela J Shaw, Hayrettin Tumani, Ole-Bjørn Tysnes, Otto Valladares, Vincenzo Silani, Leonard H van den Berg, Wouter van Rheenen, Jan H Veldink, Ulman Lindenberger, Elisabeth Steinhagen-Thiessen, Stefan Teipel, Robert Perneczky, Hakon Hakonarson, Harald Hampel, Christine A F von Arnim, Jørgen H Olsen, Vivianna M Van Deerlin, Ammar Al-Chalabi, Mathias Toft, Beate Ritz, Lars Bertram
A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis...
December 2015: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
Sara Ortega-Cubero, Oswaldo Lorenzo-Betancor, Elena Lorenzo, José A G Agúndez, Félix J Jiménez-Jiménez, Owen A Ross, Isabel Wurster, Carina Mielke, Juei-Jueng Lin, Francisco Coria, Jordi Clarimon, Mario Ezquerra, Laura Brighina, Grazia Annesi, Hortensia Alonso-Navarro, Elena García-Martin, Alex Gironell, Maria J Marti, Kuo-Chu Yueh, Zbigniew K Wszolek, Manu Sharma, Daniela Berg, Rejko Krüger, Maria A Pastor, Pau Pastor
INTRODUCTION: Essential tremor (ET) is the most frequent movement disorder in adults. Its pathophysiology is not clearly understood, however there is growing evidence showing common etiologic factors with other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases (AD, PD). Recently, a rare p.R47H substitution (rs75932628) in the TREM2 protein (triggering receptor expressed on myeloid cells 2; OMIM: *605086) has been proposed as a risk factor for AD, PD and amyotrophic lateral sclerosis (ALS)...
March 2015: Parkinsonism & related Disorders
Jun-Ichi Satoh, Naohiro Asahina, Shouta Kitano, Yoshihiro Kino
Microglia are resident mononuclear phagocytes that play a principal role in the maintenance of normal tissue homeostasis in the central nervous system (CNS). Microglia, rapidly activated in response to proinflammatory stimuli, are accumulated in brain lesions of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. The E26 transformation-specific (ETS) family transcription factor PU.1/Spi1 acts as a master regulator of myeloid and lymphoid development. PU.1-deficient mice show a complete loss of microglia, indicating that PU...
2014: Gene Regulation and Systems Biology
L-F Lue, C Schmitz, D G Walker
Microglia play major roles in initiation, coordination and execution of innate immunity in the brain. In the adult brain, these include maintenance of homeostasis, neuron and tissue repair, and eliminating infectious agents, apoptotic cells, and misfolded proteins. Some of these activities are accompanied by inflammatory reactions; and others are performed with no inflammatory effects. Under normal conditions, triggering receptor expressed on myeloid cells 2 (TREM2) belongs to the second category. It pairs with the adaptor protein DNAX-activating protein of 12kDa (DAP12) to induce phagocytosis of apoptotic neurons without inflammatory responses, and to regulate Toll-like receptor-mediated inflammatory responses, and microglial activation...
August 27, 2015: Neuroscience
Lih-Fen Lue, Christopher T Schmitz, Geidy Serrano, Lucia I Sue, Thomas G Beach, Douglas G Walker
Triggering receptor expressed by myeloid cells 2 (TREM2), a member of the immunoglobulin superfamily, has anti-inflammatory phagocytic function in myeloid cells. Several studies have shown that TREM2 gene variant rs75932628-T increased the risks for Alzheimer's disease (AD), Parkinson's disease, frontotemporal dementia and amyotrophic lateral sclerosis. It has been suggested that the risks could be resulted from the loss of TREM2 function caused by the mutation. Indeed, new evidence showed that several mutations in the immunoglobulin-like V-region led to low cell surface expression of TREM2 and reduced phagocytic function...
July 2015: Brain Pathology
Gernot Kleinberger, Yoshinori Yamanishi, Marc Suárez-Calvet, Eva Czirr, Ebba Lohmann, Elise Cuyvers, Hanne Struyfs, Nadine Pettkus, Andrea Wenninger-Weinzierl, Fargol Mazaheri, Sabina Tahirovic, Alberto Lleó, Daniel Alcolea, Juan Fortea, Michael Willem, Sven Lammich, José L Molinuevo, Raquel Sánchez-Valle, Anna Antonell, Alfredo Ramirez, Michael T Heneka, Kristel Sleegers, Julie van der Zee, Jean-Jacques Martin, Sebastiaan Engelborghs, Asli Demirtas-Tatlidede, Henrik Zetterberg, Christine Van Broeckhoven, Hakan Gurvit, Tony Wyss-Coray, John Hardy, Marco Colonna, Christian Haass
Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to Nasu-Hakola disease, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and FTD-like syndrome without bone involvement. TREM2 is an innate immune receptor preferentially expressed by microglia and is involved in inflammation and phagocytosis. Whether and how TREM2 missense mutations affect TREM2 function is unclear. We report that missense mutations associated with FTD and FTD-like syndrome reduce TREM2 maturation, abolish shedding by ADAM proteases, and impair the phagocytic activity of TREM2-expressing cells...
July 2, 2014: Science Translational Medicine
Isabelle Le Ber, Anne De Septenville, Rita Guerreiro, José Bras, Agnès Camuzat, Paola Caroppo, Serena Lattante, Philippe Couarch, Edor Kabashi, Kawtar Bouya-Ahmed, Bruno Dubois, Alexis Brice
TREM2 mutations were first identified in Nasu-Hakola disease, a rare autosomal recessive disease characterized by recurrent fractures because of bone cysts and presenile dementia. Recently, homozygous and compound heterozygous TREM2 mutations were identified in rare families with frontotemporal lobar degeneration (FTLD) but without bone involvement. We identified a p.Thr66Met heterozygous mutation in a new consanguineous Italian family. Two sibs had early onset autosomal recessive FTLD without severe bone disorders...
October 2014: Neurobiology of Aging
Shu-jun Feng, Kun Nie, Rong Gan, Jing Huang, You-wen Zhang, Li-min Wang, Jie-hao Zhao, Hong-mei Tang, Liang Gao, Rui-ming Zhu, Zhen-peng Duan, Yu-hu Zhang, Li-juan Wang
Recent studies have reported that a rare nonsynonymous variant rs75932628-T in the TREM2 gene is associated with increased risk of Alzheimer's disease and Parkinson's disease (PD) in European-descended populations. However, the association between rare TREM2 mutations and PD risk remains unknown in Chinese population. We directly sequenced exon2 of TREM2 in a cohort of 476 PD patients and 432 healthy controls from a Han Chinese population. Rs75932628-T (p.R47H) was found in 0.2% of PD cases (1/476) but in none of the controls (0/432, p = 1...
July 2014: Neurobiology of Aging
Dorit Trudler, Orly Weinreb, Silvia A Mandel, Moussa B H Youdim, Dan Frenkel
DJ-1 is an oxidative stress sensor that localizes to the mitochondria when the cell is exposed to oxidative stress. DJ-1 mutations that result in gene deficiency are linked to increased risk of Parkinson's disease (PD). Activation of microglial stress conditions that are linked to PD may result in neuronal death. We postulated that DJ-1 deficiency may increase microglial neurotoxicity. We found that down-regulation of DJ-1 in microglia using an shRNA approach increased cell sensitivity to dopamine as measured by secreted pro-inflammatory cytokines such as IL-1β and IL-6...
May 2014: Journal of Neurochemistry
Sruti Rayaprolu, Bianca Mullen, Matt Baker, Timothy Lynch, Elizabeth Finger, William W Seeley, Kimmo J Hatanpaa, Catherine Lomen-Hoerth, Andrew Kertesz, Eileen H Bigio, Carol Lippa, Keith A Josephs, David S Knopman, Charles L White, Richard Caselli, Ian R Mackenzie, Bruce L Miller, Magdalena Boczarska-Jedynak, Grzegorz Opala, Anna Krygowska-Wajs, Maria Barcikowska, Steven G Younkin, Ronald C Petersen, Nilüfer Ertekin-Taner, Ryan J Uitti, James F Meschia, Kevin B Boylan, Bradley F Boeve, Neill R Graff-Radford, Zbigniew K Wszolek, Dennis W Dickson, Rosa Rademakers, Owen A Ross
BACKGROUND: A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer's disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer's disease-related risk variant in TREM2 (rs75932628, p...
2013: Molecular Neurodegeneration
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