Cellular Regulation of Amyloid Formation in Aging and Disease

Stroo, Esther; Koopman, Mandy; Nollen, Ellen A. A.; Mata‐Cabana, Alejandro

doi:10.3389/fnins.2017.00064

Cited by 85 publications

(75 citation statements)

References 200 publications

(232 reference statements)

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“…Whereas we show that astrocytes can directly modulate neuronal health, this appeared not to be associated with alteration in the burden of protein aggregates in the brain. However, decreasing the levels of misfolded or aggregated proteins has been suggested as a therapeutic strategy [ 42 ]. Furthermore, reduction of oxidative damage can decrease degeneration [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of NF-κB in astrocytes is sufficient to delay neurodegeneration induced by proteotoxicity in neurons

Sibon

Dijkers

2018

J Neuroinflammation

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BackgroundMost neurodegenerative diseases associated with protein aggregation are hallmarked by activation of astrocytes. However, how astrocytes are activated or which signaling pathways in astrocytes contribute to pathogenesis is not clear. One long-standing question is whether the responses in astrocytes are due to stress or damage in astrocytes themselves, or because of astrocytic responses to cellular stress or damage in neurons. Here, we examine responses in astrocytes induced by expression of disease-associated, aggregation-prone proteins in other cells. We also examine the consequences of these responses in astrocytes in a model for neurodegeneration.MethodsWe first examined a role for intracellular astrocytic responses in a Drosophila model for Spinocerebellar ataxia type 3 (SCA3, also known as Machado–Joseph disease), a disease caused by expansion of the polyglutamine (polyQ) stretch in the ATXN3 gene. In this Drosophila SCA3 model, eye-specific expression of a biologically relevant portion of the ATXN3 gene, containing expanded polyQ repeats (SCA3polyQ78) was expressed. In a candidate RNAi screen in the Drosophila SCA3 model, we analyzed whether downregulation of expression of specific genes in astrocytes affected degeneration induced by SCA3polyQ78 expression in Drosophila eyes. We next examined the role of astrocytes in response to proteotoxic stress in neurons induced by SCA3polyQ78 expression or amyloid beta peptides, associated with Alzheimer’s disease.ResultsEye-specific expression of SCA3polyQ78 resulted in the presence of astrocytes in the eye, suggesting putative involvement of astrocytes in SCA3. In a candidate RNAi screen, we identified genes in astrocytes that can enhance or suppress SCA3polyQ78-induced eye degeneration. Relish, a conserved NF-κB transcription factor, was identified as an enhancer of degeneration. Activity of Relish was upregulated in our SCA3 model. Relish can exert its effect via Relish-specific AMPs, since downregulation of these AMPs attenuated degeneration. We next examined Relish signaling in astrocytes on neurodegeneration. Selective inhibition of Relish expression specifically in astrocytes extended lifespan of flies that expressed SCA3polyQ78 exclusively in neurons. Inhibition of Relish signaling in astrocytes also extended lifespan in a Drosophila model for Alzheimer’s disease.ConclusionsOur data demonstrate that astrocytes respond to proteotoxic stress in neurons, and that these astrocytic responses are important contributors to neurodegeneration. Furthermore, our data demonstrate that activation of NF-κB transcription factor Relish in astrocytes, induced by proteotoxic stress in neurons, enhances neurodegeneration, and that specific Relish inhibition in astrocytes extends lifespan. Our data provide direct evidence for cell-non-autonomous contributions of astrocytes to neurodegeneration, with possible implications for therapeutic interventions in multiple neurodegenerative diseases.Electronic supplementary materialThe online version of this article (10.1186/s1297...

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Section: Discussionmentioning

confidence: 99%

Inhibition of NF-κB in astrocytes is sufficient to delay neurodegeneration induced by proteotoxicity in neurons

Sibon

Dijkers

2018

J Neuroinflammation

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“…Generic mechanisms of amyloid induced cytotoxicity include cell membrane damage, organelle dysfunction, and impaired proteostasis that can ultimately lead to cell death [10–13]. Protein amyloid specific pathologies can also arise due to the cellular and physiological processes that are perturbed in specific tissues as well as the unique consequences linked to losing the native function of the aggregating proteins.…”

Section: Introductionmentioning

confidence: 99%

Natural product-based amyloid inhibitors

Velander

Henderson

et al. 2017

Biochemical Pharmacology

174

135

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Many chronic human diseases, including multiple neurodegenerative diseases, are associated with deleterious protein aggregates, also called protein amyloids. One common therapeutic strategy is to develop protein aggregation inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. These plant- or microorganism-extracted compounds have shown significant therapeutic potential from in vitro studies as well as in vivo animal tests. Despite the technical challenges of intrinsic disordered or partially unfolded amyloid proteins that are less amenable to characterizations by structural biology, a significant amount of research has been performed, yielding biochemical and pharmacological insights into how inhibitors function. This review aims to summarize recent progress in natural product-based amyloid inhibitors and to analyze their mechanisms of inhibition in vitro. Major classes of natural product inhibitors and how they were identified are described. Our analyses comprehensively address the molecular interactions between the inhibitors and relevant amyloidogenic proteins. These interactions are delineated at molecular and atomic levels, which include covalent, non-covalent, and metal-mediated mechanisms. In vivo animal studies and clinical trials have been summarized as an extension. To enhance natural product bioavailability in vivo, emerging work using nanocarriers for delivery has also been described. Finally, issues and challenges as well as future development of such inhibitors are envisioned.

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“…The “self‐assembling” of proteins, such as FUS/TDP43, α‐synuclein, tau, Aβ and the huntingtin into insoluble fibers that can even further aggregate is under investigation for some years, also in context to identify crowding agents initiating or supporting the molecular assembly . In Table we summarize information about crowding agents in use for in vitro LLPS assays.…”

Section: In Vivo Crystalsmentioning

confidence: 99%