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Neurofilament-Derived Peptide can Target NSCs

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Review of “The Neurofilament-Derived Peptide NFL-TBS.40-63 Targets Neural Stem Cells and Affects Their Properties” from Stem Cells Translational Medicine by Stuart P. Atkinson

Injection of bioactive agents into the cerebral fluid represents a potentially exciting strategy to therapeutically target neural stem cells (NSCs). But how can we specifically target NSCs? One possibility is a neurofilament-derived peptide (NFL-TBS.40-63) which corresponds to a neurofilament tubulin-binding site [1]. This peptide can enter and disrupt glioblastoma cells without disrupting healthy cells [2] and also promotes the differentiation and maturation of oligodendrocytes derived from newborn rats [3].

Researchers from the laboratory of Joël Eyer (Université d’Angers, France) have recently reported on their studies on the effect of this neurofilament-derived peptide on NSCs. They describe how this peptide can target NSCs in vitro and in vivo and so  may constitute a promising tool for the delivery of bioactive agents [4].

Initial analysis using newborn rat subventricular zone (SVZ) NSCs demonstrated a dose-dependent uptake of the peptide, similar to that observed in glioblastoma, as compared to a scrambled control peptide sequence. These findings highlighted the importance of the sequence and structure of the peptide for its selective entry. Additionally, these initial studies suggested that peptide uptake by NSCs occurred mainly through passive transport and not through endocytosis.

So what effect does the peptide have on NSCs? In vitro, the authors observed no major alterations to the cell cycle or microtubule network in the NSCs, although increased concentrations of the peptide led to a decrease in NSC viability and negatively affected their self-renewal, proliferation (See Figure), and differentiation potential.

Moving in vivo, stereotaxic injection of the peptide into the SVZ demonstrated the preferential accumulation in NSCs and not differentiated cells. Additionally, the peptide could pass from the cerebrospinal fluid of the lateral ventricle, through a layer of ependymal cells, and into the SVZ, demonstrating that the peptide could pass through such cell barriers and reach NSCs without detectable cytotoxicity.

The results from this study, therefore, suggest the application of the NFL-TBS.40-63 neurofilament-derived peptide as a means to target NSCs with bioactive agents. Such a strategy has the potential to drastically improve the treatment of pathological conditions such as brain tumors and neurodegenerative disorders and reduce unwanted side-effects.

References

  1. Bocquet A, Berges R, Frank R, et al. Neurofilaments bind tubulin and modulate its polymerization. J Neurosci 2009;29:11043-11054.
  2. Berges R, Balzeau J, Peterson AC, et al. A tubulin binding peptide targets glioma cells disrupting their microtubules, blocking migration, and inducing apoptosis. Mol Ther 2012;20:1367-1377.
  3. Fressinaud C and Eyer J. Neurofilament-tubulin binding site peptide NFL-TBS.40-63 increases the differentiation of oligodendrocytes in vitro and partially prevents them from lysophosphatidyl choline toxiciy. J Neurosci Res 2014;92:243-253.
  4. Lepinoux-Chambaud C, Barreau K, and Eyer J. The Neurofilament-Derived Peptide NFL-TBS.40-63 Targets Neural Stem Cells and Affects Their Properties. Stem Cells Transl Med 2016;5:901-913.