Prion-like properties of disease-relevant proteins in amyotrophic lateral sclerosis

Abstract

The hallmark of age-related neurodegenerative diseases is the appearance of cellular protein deposits and spreading of this pathology throughout the central nervous system. Growing evidence has shown the involvement and critical role of proteins with prion-like properties in the formation of these characteristic cellular aggregates. Prion-like domains of such proteins with their proposed function in the organization of membraneless organelles are prone for misfolding and promoting further aggregation. Spreading of these toxic aggregates between cells and across tissues can explain the progression of clinical phenotypes and pathology in a stereotypical manner, characteristic for almost every neurodegenerative disease. Here, we want to review the current evidence for the role of prion-like mechanisms in classical neurodegenerative diseases and ALS in particular. We will also discuss an intriguingly central role of the protein TDP-43 in the majority of cases of this devastating disease.

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Acknowledgements

This work was supported, in part, the NOMIS foundation and the Helmholtz Virtual Institute “RNA dysmetabolism in ALS and FTD (VH-VI-510)” to A.H.

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Correspondence to A. Hermann.

Appendix

Appendix

How to treat prions

Potential therapeutic strategies to target neurodegenerative diseases with prion-like mechanisms.

Neutralizing antibodies

In AD, several antibodies targeting β-amyloid have been developed. Recently, aducanumab, an antibody targeting aggregated β-amyloid, was shown to reduce amyloid load in PET imaging in human patients (Sevigny et al. 2016).

The potential effectiveness of targeted antibody therapy has also been demonstrated in mouse models for tau (Chai et al. 2011; Yanamandra et al. 2013) and α-synuclein (Games et al. 2014; Spencer et al. 2017; Tran et al. 2014). Zhou et al. summarized that the immunotherapy with anti-GA antibodies could be a possible treatment for patients with poly-GA pathology in C9orf72 disease (Zhou et al. 2017).

Resolution of the aggregates

Protein disaggregases to counter aberrant phase transition via diverse proteins like Hsp110, Hsp70, Hsp40 and further have been reviewed by Harrison and Shorter (Harrison and Shorter 2017). Addressing ALS, overexpression of chaperone Hsp 110 increased the median survival in a transgenetic G85R SOD1YFP mouse model (Nagy et al. 2016).

Silencing mechanisms

Silencing of ALS-causing genes is of debate, however—at least in cases of TDP43 and FUS—reduced expression of the protein itself could be harmful (Bhandare and Ramaswamy 2016). In addition, there is the possibility of allele-specific knockdown of mutant TDP-43 via siRNA (Nishimura et al. 2014). Furthermore, the silencing of SOD1 via microRNA delayed disease and death in an SOD1(G93A) mice (Borel et al. 2016) and is currently in phase 2 studies. Possible silencing mechanisms for SOD1 in ALS like siRNA, microRNA, and anti-sense oligonucleotides are reviewed by van Sundert et al. (van Zundert and Brown 2017).

Inhibiting necroptosis

By blocking necroptosis, a possible mechanism of aggregate release could be eliminated, and furthermore, this could block the toxicity of the glia component in ALS demonstrated by Re and colleagues (Re et al. 2014).

Blocking exosomes

Investigation of blocking the release via exosoms with, for example, neutral-sphingomyelinase-2-inhibitor showed different results. Blocking exosomes in a tau mouse model led to decreased tau propagation in the brains (Asai et al. 2015). Whereas blocking exosoms in TDP-43 ALS caused increasing cytoplasmic aggregates in vitro and symptom exacerbation in vivo in a TDP-43 mouse model (Smethurst et al. 2016).

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Bräuer, S., Zimyanin, V. & Hermann, A. Prion-like properties of disease-relevant proteins in amyotrophic lateral sclerosis. J Neural Transm 125, 591–613 (2018). https://doi.org/10.1007/s00702-018-1851-y

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Keywords

  • Neurodegenerative disease
  • Amyotrophic lateral sclerosis
  • Motor neuron disease
  • TDP-43
  • FUS
  • Prion-like properties
  • Disease spreading
  • Strains