Mechanisms of Immune Activation by c9orf72-Expansions in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

被引:23
作者
Trageser, Kyle J. [1 ]
Smith, Chad [1 ]
Herman, Francis J. [1 ]
Ono, Kenjiro [2 ]
Pasinetti, Giulio Maria [1 ,3 ]
机构
[1] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA
[2] Showa Univ, Dept Med, Div Neurol, Sch Med, Tokyo, Japan
[3] JJ Peters VA Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY 10468 USA
关键词
amyotrophic lateral sclerosis (ALS); frontotemporal dementia (FTD); C9orf72; innate immunity; TDP-43; reactive oxygen species (ROS); therapeutics; microglia; HEXANUCLEOTIDE REPEAT EXPANSION; TRANSGENIC MOUSE MODEL; THERAPEUTIC TARGETS; STRESS GRANULES; GGGGCC REPEAT; C9ORF72; MICROGLIA; DISEASE; ALS; EDARAVONE;
D O I
10.3389/fnins.2019.01298
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with overlapping pathomechanisms, neurobehavioral features, and genetic etiologies. Individuals diagnosed with either disorder exhibit symptoms within a clinical spectrum. Symptoms of ALS involve neuromusculature deficits, reflecting upper and lower motor neurodegeneration, while the primary clinical features of FTD are behavioral and cognitive impairments, reflecting frontotemporal lobar degeneration. An intronic G(4)C(2) hexanucleotide repeat expansion (HRE) within the promoter region of chromosome 9 open reading frame 72 (C9orf72) is the predominant monogenic cause of both ALS and FTD. While the heightened risk to develop ALS/FTD in response to C9orf72 expansions is well-established, studies continue to define the precise mechanisms by which this mutation elicits neurodegeneration. Studies show that G(4)C(2) expansions undergo repeat-associated non-ATG dependent (RAN) translation, producing dipeptide repeat proteins (DRPs) with varying toxicities. Accumulation of DRPs in neurons, in particular arginine containing DRPs, have neurotoxic effects by potently impairing nucleocytoplasmic transport, nucleotide metabolism, lysosomal processes, and cellular metabolic pathways. How these pathophysiological effects of C9orf72 expansions engage and elicit immune activity with additional neurobiological consequences is an important line of future investigations. Immunoreactive microglia and elevated levels of peripheral inflammatory cytokines noted in individuals with C9orf72 ALS/FTD provide evidence that persistent immune activation has a causative role in the progression of each disorder. This review highlights the current understanding of the cellular, proteomic and genetic substrates through which G(4)C(2) HREs may elicit detrimental immune activity, facilitating region-specific neurodegeneration in C9orf72 mediated ALS/FTD. We in particular emphasize interactions between intracellular pathways induced by C9orf72 expansions and innate immune inflammasome complexes, intracellular receptors responsible for eliciting inflammation in response to cellular stress. A further understanding of the intricate, reciprocal relationship between the cellular and molecular pathologies resulting from C9orf72 HREs and immune activation may yield novel therapeutics for ALS/FTD, which currently have limited treatment strategies.
引用
收藏
页数:15
相关论文
共 118 条
[1]   C9orf72 expansion within astrocytes reduces metabolic flexibility in amyotrophic lateral sclerosis [J].
Allen, Scott P. ;
Hall, Benjamin ;
Woof, Ryan ;
Francis, Laura ;
Gatto, Noemi ;
Shaw, Allan C. ;
Myszczynska, Monika ;
Hemingway, Jordan ;
Coldicott, Ian ;
Willcock, Amelia ;
Job, Lucy ;
Hughes, Rachel M. ;
Boschian, Camilla ;
Bayatti, Nadhim ;
Heath, Paul R. ;
Bandmann, Oliver ;
Mortiboys, Heather ;
Ferraiuolo, Laura ;
Shaw, Pamela J. .
BRAIN, 2019, 142 :3771-3790
[2]  
[Anonymous], AMYOTROPH LATERAL SC
[3]  
[Anonymous], GLIA
[4]   Aspirin and salicylate protect against MPTP-induced dopamine depletion in mice [J].
Aubin, N ;
Curet, O ;
Deffois, A ;
Carter, C .
JOURNAL OF NEUROCHEMISTRY, 1998, 71 (04) :1635-1642
[5]   C9orf72-mediated ALS and FTD: multiple pathways to disease [J].
Balendra, Rubika ;
Isaacs, Adrian M. .
NATURE REVIEWS NEUROLOGY, 2018, 14 (09) :544-558
[6]   Aspirin Efficacy in Primary Prevention: A Meta-analysis of Randomized Controlled Trials [J].
Barbarawi, Mahmoud ;
Kheiri, Babikir ;
Zayed, Yazan ;
Gakhal, Inderdeep ;
Al-Abdouh, Ahmad ;
Barbarawi, Owais ;
Rashdan, Laith ;
Rizk, Fatima ;
Bachuwa, Ghassan ;
Alkotob, Mohammad Luay .
HIGH BLOOD PRESSURE & CARDIOVASCULAR PREVENTION, 2019, 26 (04) :283-291
[7]   Beneficial effects of lysine acetylsalicylate, a soluble salt of aspirin, on motor performance in a transgenic model of amyotrophic lateral sclerosis [J].
Barnéoud, P ;
Curet, O .
EXPERIMENTAL NEUROLOGY, 1999, 155 (02) :243-251
[8]   Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis [J].
Beers, David R. ;
Henkel, Jenny S. ;
Xiao, Qin ;
Zhao, Weihua ;
Wang, Jinghong ;
Yen, Albert A. ;
Siklos, Laszlo ;
McKercher, Scott R. ;
Appel, Stanley H. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (43) :16021-16026
[9]   Immune dysregulation in amyotrophic lateral sclerosis: mechanisms and emerging therapies [J].
Beers, David R. ;
Appel, Stanley H. .
LANCET NEUROLOGY, 2019, 18 (02) :211-220
[10]   Brain Energy Metabolism: Focus on Astrocyte-Neuron Metabolic Cooperation [J].
Belanger, Mireille ;
Allaman, Igor ;
Magistretti, Pierre J. .
CELL METABOLISM, 2011, 14 (06) :724-738