Neuron-to-Neuron Transfer of FUS in Drosophila Primary Neuronal Culture Is Enhanced by ALS-Associated Mutations

Feuillette, Sébastien; Delarue, Morgane; Riou, Gaëtan; Gaffuri, Anne Lise; Wu, Jane Y.; Lenkei, Zsolt; Boyer, Olivier; Frébourg, Thierry; Campion, Dominique; Lecourtois, Magalie

doi:10.1007/s12031-017-0908-y

Cited by 13 publications

(7 citation statements)

References 38 publications

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“…Cytoplasmic FUS accumulation and a severe motor phenotype were observed in transgenic mouse models that express aggregate-prone FUS variants lacking the ability to recognize and bind RNA (Shelkovnikova et al, 2013; Robinson et al, 2015). Additionally, as seen with TDP-43, there are indications of a propagating mechanism of disease in FUS-ALS, possibly mediated by its prion-like protein domain (Lee and Kim, 2015; Feuillette et al, 2017). There is also evidence that soluble cytoplasmic FUS may be toxic.…”

Section: Als Associated Genesmentioning

confidence: 99%

ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now?

et al. 2019

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The scientific landscape surrounding amyotrophic lateral sclerosis (ALS) continues to shift as the number of genes associated with the disease risk and pathogenesis, and the cellular processes involved, continues to grow. Despite decades of intense research and over 50 potentially causative or disease-modifying genes identified, etiology remains unexplained and treatment options remain limited for the majority of ALS patients. Various factors have contributed to the slow progress in understanding and developing therapeutics for this disease. Here, we review the genetic basis of ALS, highlighting factors that have contributed to the elusiveness of genetic heritability. The most commonly mutated ALS-linked genes are reviewed with an emphasis on disease-causing mechanisms. The cellular processes involved in ALS pathogenesis are discussed, with evidence implicating their involvement in ALS summarized. Past and present therapeutic strategies and the benefits and limitations of the model systems available to ALS researchers are discussed with future directions for research that may lead to effective treatment strategies outlined.

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Section: Als Associated Genesmentioning

confidence: 99%

ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now?

et al. 2019

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“…For example, aggregates of neurodegenerative disease-linked proteins can “infect” cell models causing endogenous proteins to aggregate (Furukawa et al, 2011; Karpowicz et al, 2017; Olsson et al, 2018). Likewise, ALS-linked proteins are capable of being transferred between cultured cells (Feiler et al, 2015; Feuillette et al, 2017). Likewise, the yeast protein Sup35 can propagate as a prion via horizontal transfer between cultured mammalian cells (Krammer et al, 2009; Liu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Yeast Models of Prion-Like Proteins That Cause Amyotrophic Lateral Sclerosis Reveal Pathogenic Mechanisms

Monahan

Rhoads

Yee

et al. 2018

Front. Mol. Neurosci.

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Many proteins involved in the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS) are remarkably similar to proteins that form prions in the yeast Saccharomyces cerevisiae. These ALS-associated proteins are not orthologs of yeast prion proteins, but are similar in having long, intrinsically disordered domains that are rich in hydrophilic amino acids. These so-called prion-like domains are particularly aggregation-prone and are hypothesized to participate in the mislocalization and misfolding processes that occur in the motor neurons of ALS patients. Methods developed for characterizing yeast prions have been adapted to studying ALS-linked proteins containing prion-like domains. These yeast models have yielded major discoveries, including identification of new ALS genetic risk factors, new ALS-causing gene mutations and insights into how disease mutations enhance protein aggregation.

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“…While for the other ALS-related proteins such as SOD1 and TDP-43 a prion-like behavior is well established, data indicating an intercellular spreading mechanism for FUS and C9orf72-derived DPRs is only recently emerging (Nomura et al, 2014 ; Feuillette et al, 2017 ; Zhou et al, 2017 ; Morón-Oset et al, 2019 ). However, since chaperones are known to be able to modulate the toxicity of FUS and C9orf72 (Deng et al, 2015 ; Cristofani et al, 2018 ), it is highly likely that they would also affect their transmission in one way or the other.…”

Section: The Role Of Chaperones In Prion-like Propagationmentioning

confidence: 99%

Molecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases

Tittelmeier

Nachman

Nussbaum-Krammer

2020

Front. Aging Neurosci.

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Aberrant accumulation of misfolded proteins into amyloid deposits is a hallmark in many age-related neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Pathological inclusions and the associated toxicity appear to spread through the nervous system in a characteristic pattern during the disease. This has been attributed to a prion-like behavior of amyloid-type aggregates, which involves self-replication of the pathological conformation, intercellular transfer, and the subsequent seeding of native forms of the same protein in the neighboring cell. Molecular chaperones play a major role in maintaining cellular proteostasis by assisting the (re)-folding of cellular proteins to ensure their function or by promoting the degradation of terminally misfolded proteins to prevent damage. With increasing age, however, the capacity of this proteostasis network tends to decrease, which enables the manifestation of neurodegenerative diseases. Recently, there has been a plethora of studies investigating how and when chaperones interact with disease-related proteins, which have advanced our understanding of the role of chaperones in protein misfolding diseases. This review article focuses on the steps of prion-like propagation from initial misfolding and self-templated replication to intercellular spreading and discusses the influence that chaperones have on these various steps, highlighting both the positive and adverse consequences chaperone action can have. Understanding how chaperones alleviate and aggravate disease progression is vital for the development of therapeutic strategies to combat these debilitating diseases.

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Neuron-to-Neuron Transfer of FUS in Drosophila Primary Neuronal Culture Is Enhanced by ALS-Associated Mutations

Cited by 13 publications

References 38 publications

ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now?

ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now?

Yeast Models of Prion-Like Proteins That Cause Amyotrophic Lateral Sclerosis Reveal Pathogenic Mechanisms

Molecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases

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