Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report

Nelson, Peter T.; Dickson, Dennis W.; Trojanowski, John Q.; Jack, Clifford R.; Boyle, Patricia A.; Arfanakis, Konstantinos; Rademakers, Rosa; Alafuzoff, Irina; Attems, Johannes; Brayne, Carol; Coyle‐Gilchrist, Ian; Chui, Helena C.; Fardo, David W.; Flanagan, Margaret E.; Halliday, Glenda M.; Hokkanen, Suvi R. K.; Hunter, Sally; Jicha, Gregory A.; Katsumata, Yuriko; Kawas, Claudia H.; Keene, C. Dirk; Kovács, Gábor G.; Kukull, Walter A.; Levey, Aĺlan I.; Makkinejad, Nazanin; Montine, Thomas J.; Murayama, Shigeo; Murray, Melissa E.; Nag, Sukriti; Rissman, Robert A.; Seeley, William W.; Sperling, Reisa A.; White, Charles L.; Yu, Lei; Schneider, Julie A.

doi:10.1093/brain/awz099

Cited by 917 publications

(971 citation statements)

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“…There is increasing evidence of TDP-43 pathology in the hippocampal neurons of patients with Alzheimer's disease and correlated with ApoE4 alleles (58)(59)(60). LATE, a recently defined dementia in the oldest elderly, is a neurological disorder of remarkable TDP-43 cytoplasmic aggregates (18). Acetylated, RNA-binding deficient TDP-43 is present in the pathological TDP-43 aggregates (27).…”

Section: Discussionmentioning

confidence: 99%

“…TAR DNA-binding protein 43 (TDP-43) is a common pathological hallmark shared by several agerelated neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) (16), frontotemporal dementia (FTD) (15), Alzheimer's disease (AD) (17), and the recently defined ADlike variant named "LATE" (limbic predominant age-related TDP-43 encephalopathy) in the oldest individuals (18). TDP-43 functions in pre-mRNA maturation, including splicing (19).…”

Section: Mislocalization and Aggregation Of The Heterogeneous Nuclearmentioning

confidence: 99%

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TDP-43 and HSP70 phase separate into anisotropic, intranuclear liquid spherical annuli

Gasior

et al. 2020

Preprint

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One Sentence Summary:Acetylation of TDP-43 drives its phase separation into spherical annuli that form a liquid-insidea-liquid-inside-a-liquid. AbstractThe RNA binding protein TDP-43 naturally phase separates within cell nuclei and forms cytoplasmic aggregates in age-related neurodegenerative diseases. Here we show that acetylation-mediated inhibition of TDP-43 binding to RNA produces co-de-mixing of acetylated and unmodified TDP-43 into symmetrical, intranuclear spherical annuli whose shells and cores have liquid properties. Shells are anisotropic, like liquid crystals. Consistent with our modelling predictions that annulus formation is driven by components with strong self-interactions but weak interaction with TDP-43, the major components of annuli cores are identified to be HSP70 family proteins, whose chaperone activity is required to maintain liquidity of the core. Proteasome inhibition, mimicking reduction in proteasome activity during aging, induces TDP-43-containing annuli in neurons in rodents. Thus, we identify that TDP-43 phase separation is regulated by acetylation, proteolysis, and ATPase-dependent chaperone activity of HSP70.A seminal discovery in the last decade has been recognition that large biological molecules, especially RNA binding proteins, can undergo liquid-liquid phase separation (LLPS), resembling oil droplets in vinegar. Under certain physical conditions, proteins, nucleic acids, or a mixture of both in a complex solution can form two phases, a condensed de-mixed phase and more dilute aqueous phase (1). Inside the cell, proteins and/or nucleic acids de-mix into a condensed phase to form membraneless organelles which have been proposed to promote biological functions (2).One membraneless organelle is the nucleolus, first described in the early 1800's and now recognized to be composed of proteins that undergo LLPS (3-5). Discovery that P-granules are de-mixed compartments with liquid behaviour brought widespread recognition to LLPS and its ability to mediate subcellular compartmentalization in a biological context (6). Phase separation has been also proposed for heterochromatin and RNA bodies (1, 6, 7). LLPS potentially underlies the operational principle governing formation of important organelles and structures, such as centrosomes, nuclear pore complexes, and super enhancers (8-10).Few mechanisms to modulate intracellular LLPS have been identified. Disease-causing mutations of proteins such as FUS (11) and HNRNPA2B1 (12) alter their LLPS behaviors in vitro, but the physiological or pathological relevance of their intracellular LLPS has not been fully elucidated. Random, multivalent interactions among intrinsically disordered, low complexity domains (LCDs) of proteins are a major driving force for LLPS in vitro. Oligomerization of other domains is thought to be required for LLPS in vivo (13). The inherent randomness of multivalent interactions (14) favors a model of disordered alignment -a conventional liquid phase in which molecules randomly move. The evidence is compelling that multi...

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Section: Discussionmentioning

confidence: 99%

Section: Mislocalization and Aggregation Of The Heterogeneous Nuclearmentioning

confidence: 99%

TDP-43 and HSP70 phase separate into anisotropic, intranuclear liquid spherical annuli

Gasior

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…It has also been suggested that there is a spectrum of diseases that may be diagnosed as AD (Dubois et al, 2010). Of note, a recent report on limbic‐predominant age‐related TDP‐43 encephalopathy, which appears in patients above 80 years old and shows clinical features of AD‐like symptoms without clear AD histopathology hallmarks as described below (Nelson et al, 2019). Therefore, while cognitive impairment may be similar, involvement of different factors that attribute to AD may differ in individuals leading to different type of disease.…”

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confidence: 97%

Alzheimer's disease: A need for personalized therapeutic approaches

Frenkel

2020

Drug Development Research

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“…The mechanism is often attributed to glial cell dysfunction, [28][29][30][31][32][33] although there is no agreement on the glial cell changes that result in downstream findings. [34][35][36][37][38] This type of model ( Figure 3) can be represented by a single fundamental upstream mechanism causing multiple downstream findings, including amyloid plaque, tau tangles, mitochondrial dysfunction, 39 lipid processing, 40 TDP-43 proteinopathy, 41 immune function, and synaptic loss. 42 A more general model would encompass all dementias, offering an underlying and shared upstream mechanism expressed variably in specific dementias.…”

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confidence: 99%

A unified model of dementias and age‐related neurodegeneration

Fossel

2020

Alzheimer's & Dementia

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Those working with Alzheimer's and other dementias have been frustrated by the implacability of these diseases. Regardless of limited symptomatic treatment, 1 there are no proven disease-modifying interventions. Despite huge and growing costs of care, 2 a pipeline of candidate drugs, 3 >400 registered trials, 4 tens of thousands of patients, 5 billions of dollars in both US federal 6 and pharmaceutical company investment, 7,8 more than a century of clinical expertise, and thousands of professional careers, dozens of pharmaceutical and biotechnology firms have foundered and failed 9 in attempts to prevent, slow, or alter the course of the dementias.This article presents a novel model to explain the relationships between age-related neurodegenerative disorders (eg, dementias) and the underlying molecular mechanisms of the aging process. The hypothesis is prompted by the fact that accepted conceptual models have failed to yield effective interventions for Alzheimer's or other dementias. 10 This article is a specific response to the Alzheimer's & Dementia editorial of November 2015, 11 which called for a systemic re-evaluation of our current models and their ability to answer fundamental questions regarding complex brain disorders and their relationship to clinical dementia, as well as the failure to yield effective clinical interventions.The article is divided into three parts. The first part explores current models of age-related neurogenerative diseases. The second part proposes a specific model and details both its working and its implications.The third part applies the model to answering the 10 key questions proposed by the Alzheimer's & Dementia editorial. The intent is to provide a conceptual model that accords with known data and proposes a novel point of clinical intervention. The model is intended to provoke discussion and provide a point of departure, rather than to offer a complete and final model for age-related neurodegenerative disease. The value of any such model rests on the outcome of clinical trials, but the model offers potentially innovative pathways to such trials. Current dementia modelsAlthough there is no general explanation for the failure to identify an effective intervention, there is growing consensus that a major factor is the lack of a comprehensive model for the dementias. 12 Over the past century, 13 several models have attained varying degrees of acceptance.Such models generally assume (or imply) a predominant single cause of Alzheimer's disease (AD; Figure 1).Such models suggest that, although several factors may contribute to the pathology, most Alzheimer's pathology results from a single predominant cause, such as amyloid plaque. In Figure 1, A (the predominant cause) is the leading causal factor, whereas B, C, D, and E represent contributing (but less significant or even incidental) factors.Until recently, the foremost among such explanations has been amyloid (A ) theory, [14][15][16][17] in various iterations. Other candidates have been tau tangles, 18-20 mitochondrial dysfun...

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Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report

Cited by 917 publications

References 272 publications

TDP-43 and HSP70 phase separate into anisotropic, intranuclear liquid spherical annuli

TDP-43 and HSP70 phase separate into anisotropic, intranuclear liquid spherical annuli

Alzheimer's disease: A need for personalized therapeutic approaches

A unified model of dementias and age‐related neurodegeneration

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