Gel-like inclusions of C-terminal fragments of TDP-43 sequester and inhibit proteasomes in neurons

TDP-43 inclusions enriched in C-terminal fragments of ~25kDa ("TDP-25") are associated with neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we analyzed gain-of-function mechanisms of TDP-25 combining cryo-electron tomography, proteomics and functional assays. TDP-25 inclusions are amorphous with gel-like biophysical properties and sequester proteasomes adopting exclusively substrate-processing conformations. This leads to proteostasis impairment, further enhanced by pathogenic mutations. These findings bolster the importance of proteasome dysfunction in ALS/FTD.

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Glial Cell Dysfunction in C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Cells ◽

10.3390/cells10020249 ◽

2021 ◽

Vol 10 (2) ◽

pp. 249

Author(s):

Mehdi Ghasemi ◽

Kiandokht Keyhanian ◽

Catherine Douthwright

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Signaling Pathways ◽

Frontotemporal Dementia ◽

Glial Cell ◽

Glial Cells ◽

Chromosome 9 ◽

Loss Of Function ◽

Gain Of Function ◽

Cell Dysfunction ◽

Lateral Sclerosis

Since the discovery of the chromosome 9 open reading frame 72 (C9orf72) repeat expansion mutation in 2011 as the most common genetic abnormality in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) and frontotemporal dementia (FTD), progress in understanding the signaling pathways related to this mutation can only be described as intriguing. Two major theories have been suggested—(i) loss of function or haploinsufficiency and (ii) toxic gain of function from either C9orf72 repeat RNA or dipeptide repeat proteins (DPRs) generated from repeat-associated non-ATG (RAN) translation. Each theory has provided various signaling pathways that potentially participate in the disease progression. Dysregulation of the immune system, particularly glial cell dysfunction (mainly microglia and astrocytes), is demonstrated to play a pivotal role in both loss and gain of function theories of C9orf72 pathogenesis. In this review, we discuss the pathogenic roles of glial cells in C9orf72 ALS/FTD as evidenced by pre-clinical and clinical studies showing the presence of gliosis in C9orf72 ALS/FTD, pathologic hallmarks in glial cells, including TAR DNA-binding protein 43 (TDP-43) and p62 aggregates, and toxicity of C9orf72 glial cells. A better understanding of these pathways can provide new insights into the development of therapies targeting glial cell abnormalities in C9orf72 ALS/FTD.

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Modeling C9orf72-Related Frontotemporal Dementia and Amyotrophic Lateral Sclerosis in Drosophila

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.770937 ◽

2021 ◽

Vol 15 ◽

Author(s):

Joanne L. Sharpe ◽

Nikki S. Harper ◽

Duncan R. Garner ◽

Ryan J. H. West

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Loss Of Function ◽

Gain Of Function ◽

Dipeptide Repeat Proteins ◽

Repeat Proteins ◽

Individual Contributions ◽

The Individual ◽

Lateral Sclerosis ◽

Dipeptide Repeat

An intronic hexanucleotide (GGGGCC) expansion in the C9orf72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In the decade following its discovery, much progress has been made in enhancing our understanding of how it precipitates disease. Both loss of function caused by reduced C9orf72 transcript levels, and gain of function mechanisms, triggered by the production of repetitive sense and antisense RNA and dipeptide repeat proteins, are thought to contribute to the toxicity. Drosophila models, with their unrivaled genetic tractability and short lifespan, have played a key role in developing our understanding of C9orf72-related FTD/ALS. There is no C9orf72 homolog in fly, and although this precludes investigations into loss of function toxicity, it is useful for elucidating mechanisms underpinning gain of function toxicity. To date there are a range of Drosophila C9orf72 models, encompassing different aspects of gain of function toxicity. In addition to pure repeat transgenes, which produce both repeat RNA and dipeptide repeat proteins (DPRs), RNA only models and DPR models have been generated to unpick the individual contributions of RNA and each dipeptide repeat protein to C9orf72 toxicity. In this review, we discuss how Drosophila models have shaped our understanding of C9orf72 gain of function toxicity, and address opportunities to utilize these models for further research.

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Amyotrophic lateral sclerosis with frontotemporal dementia (ALS-FTD) syndrome as a phenotype of Creutzfeldt-Jakob disease (CJD)? A case report

Journal of the Neurological Sciences ◽

10.1016/j.jns.2016.10.038 ◽

2017 ◽

Vol 372 ◽

pp. 444-446 ◽

Cited By ~ 7

Author(s):

Hiroaki Yaguchi ◽

Akiko Takeuchi ◽

Kazuhiro Horiuchi ◽

Ikuko Takahashi ◽

Shinnichi Shirai ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Case Report ◽

Frontotemporal Dementia ◽

Jakob Disease ◽

Lateral Sclerosis

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Novel TARDBP missense mutation caused familial amyotrophic lateral sclerosis with frontotemporal dementia and parkinsonism

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2021.05.017 ◽

2021 ◽

Author(s):

Sheng Chen ◽

Rui-Ling Zhou ◽

Wei Zhang ◽

Chun-Hui Che ◽

Shu-Yan Feng ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Missense Mutation ◽

Familial Amyotrophic Lateral Sclerosis ◽

Lateral Sclerosis

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Frontotemporal dementia and amyotrophic lateral sclerosis: Revisiting one of the first case reports with neuropathological examination

Dementia & Neuropsychologia ◽

10.1590/s1980-57642014dn81000013 ◽

2014 ◽

Vol 8 (1) ◽

pp. 83-86 ◽

Cited By ~ 2

Author(s):

Ricardo Nitrini

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Motor Neurons ◽

Case Reports ◽

Rare Event ◽

Motor Impairments ◽

Late 20Th Century ◽

First Case ◽

Lateral Sclerosis ◽

Neuropathological Examination

ABSTRACT The occurrence of dementia in amyotrophic lateral sclerosis (ALS) was only widely recognized in the late 20th century. Hitherto, it was believed that dementia was a rare event due to the fortuitous association with other diseases. In 1924, Kostantin Nikolaevich Tretiakoff and Moacyr de Freitas Amorim reported a case of dementia with features of frontotemporal dementia (FTD) that preceded the motor signs of ALS. Neuropathological examination confirmed ALS and found no signs of other dementia-causing diseases. The authors hypothesized that dementia was part of ALS and recommended the search for signs of involvement of motor neurons in cases of dementia with an ill-defined clinical picture, a practice currently accepted in the investigation of cases of FTD. This was one of the first descriptions of dementia preceding the motor impairments of ALS and was published in Portuguese and French in Memórias do Hospício de Juquery.

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Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity

Life Science Alliance ◽

10.26508/lsa.202101185 ◽

2021 ◽

Vol 5 (3) ◽

pp. e202101185

Author(s):

Irene Riera-Tur ◽

Tillman Schäfer ◽

Daniel Hornburg ◽

Archana Mishra ◽

Miguel da Silva Padilha ◽

...

Keyword(s):

Protein Aggregation ◽

Protein Trafficking ◽

Cell Biology ◽

Electron Tomography ◽

Lysosomal Storage ◽

Gain Of Function ◽

Cryo Electron Tomography ◽

A Subunit ◽

Late Stages ◽

Β Sheet

The autophagy-lysosomal pathway is impaired in many neurodegenerative diseases characterized by protein aggregation, but the link between aggregation and lysosomal dysfunction remains poorly understood. Here, we combine cryo-electron tomography, proteomics, and cell biology studies to investigate the effects of protein aggregates in primary neurons. We use artificial amyloid-like β-sheet proteins (β proteins) to focus on the gain-of-function aspect of aggregation. These proteins form fibrillar aggregates and cause neurotoxicity. We show that late stages of autophagy are impaired by the aggregates, resulting in lysosomal alterations reminiscent of lysosomal storage disorders. Mechanistically, β proteins interact with and sequester AP-3 μ1, a subunit of the AP-3 adaptor complex involved in protein trafficking to lysosomal organelles. This leads to destabilization of the AP-3 complex, missorting of AP-3 cargo, and lysosomal defects. Restoring AP-3μ1 expression ameliorates neurotoxicity caused by β proteins. Altogether, our results highlight the link between protein aggregation, lysosomal impairments, and neurotoxicity.

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Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.767041 ◽

2021 ◽

Vol 14 ◽

Author(s):

Elise Liu ◽

Léa Karpf ◽

Delphine Bohl

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Immune System ◽

Frontotemporal Dementia ◽

Immune Cells ◽

Immune Cell ◽

Current Knowledge ◽

Cell Types ◽

Induced Pluripotent ◽

Different Cell Types ◽

Lateral Sclerosis

Inflammation is a shared hallmark between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). For long, studies were conducted on tissues of post-mortem patients and neuroinflammation was thought to be only bystander result of the disease with the immune system reacting to dying neurons. In the last two decades, thanks to improving technologies, the identification of causal genes and the development of new tools and models, the involvement of inflammation has emerged as a potential driver of the diseases and evolved as a new area of intense research. In this review, we present the current knowledge about neuroinflammation in ALS, ALS-FTD, and FTD patients and animal models and we discuss reasons of failures linked to therapeutic trials with immunomodulator drugs. Then we present the induced pluripotent stem cell (iPSC) technology and its interest as a new tool to have a better immunopathological comprehension of both diseases in a human context. The iPSC technology giving the unique opportunity to study cells across differentiation and maturation times, brings the hope to shed light on the different mechanisms linking neurodegeneration and activation of the immune system. Protocols available to differentiate iPSC into different immune cell types are presented. Finally, we discuss the interest in studying monocultures of iPS-derived immune cells, co-cultures with neurons and 3D cultures with different cell types, as more integrated cellular approaches. The hope is that the future work with human iPS-derived cells helps not only to identify disease-specific defects in the different cell types but also to decipher the synergistic effects between neurons and immune cells. These new cellular tools could help to find new therapeutic approaches for all patients with ALS, ALS-FTD, and FTD.

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