Thymosin beta 4-Induced Autophagy Increases Cholinergic Signaling in PrP (106–126)-Treated HT22 Cells
Prion protein peptide (PrP) has been associated with neurotoxicity in brain cells and progression of prion diseases due to spongiform degeneration and accumulation of the infectious scrapie prion protein (PrPSc). Autophagy has been shown to provide protective functions for neurodegenerative diseases, including prion disease. Thymosin beta 4 (Tβ4) plays a key role in the nervous system, providing a neuronal growth effect that includes motility, neurite outgrowth, and proliferation. However, the effect of Tβ4 on autophagy in prion disease has not been investigated. In this study, we investigated the neuroprotective effects of Tβ4, an activator of autophagy, in cholinergic signaling activation in PrP (106–126)-treated HT22 cells. We found that Tβ4-induced autophagy markers, LC3A/B and Beclin1, were protective against PrP-induced neurotoxicity. Interestingly, a balance between autophagy markers and autophagy pathway factors (AKT, p-AKT, mTOR, and p-mTOR) was maintained by Tβ4 competitively against each protein factors reacted to PrP (106–126). The cholinergic signaling markers ChTp and AChE, which play an important role in the brain, were maintained by Tβ4 competitively against each protein factors reacted to PrP (106–126). However, these results were reversed by 3-MA, an autophagy inhibitor. Taken together, our results indicate that Tβ4 has cholinergic signaling activities through the induction of autophagy. Thus, Tβ4 may be to a potential therapeutic agent for preventing neurodegenerative diseases.
KeywordsThymosin beta 4 Autophagy Cholinergic signaling Prion protein
This work was supported by a grant from the National Research Foundation of Korea, funded by the Korean government (NRF-2015R1D1A1A01057696).
- Heiseke A, Aguib Y, Schatzl HM (2010) Autophagy, prion infection and their mutual interactions. Curr Issues Mol Biol 12:87–97Google Scholar
- Nakagaki T, Satoh K, Ishibashi D, Fuse T, Sano K, Kamatari YO, Kuwata K, Shigematsu K, Iwamaru Y, Takenouchi T, Kitani H, Nishida N, Atarashi R (2013) FK506 reduces abnormal prion protein through the activation of autolysosomal degradation and prolongs survival in prion-infected mice. Autophagy 9:1386–1394. https://doi.org/10.4161/auto.25381 CrossRefGoogle Scholar
- Perry EK, Irving D, Kerwin JM, McKeith IG, Thompson P, Collerton D, Fairbairn AF, Ince PG, Morris CM, Cheng AV, Perry RH (1993) Cholinergic transmitter and neurotrophic activities in Lewy body dementia: similarity to Parkinson’s and distinction from Alzheimer disease. Alzheimer Dis Assoc Disord 7:69–79CrossRefGoogle Scholar
- Schatzl HM et al (1997) A hypothalamic neuronal cell line persistently infected with scrapie prions exhibits apoptosis. J Virol 71:8821–8831Google Scholar
- Sikorska B, Liberski PP, Brown P (2007) Neuronal autophagy and aggresomes constitute a consistent part of neurodegeneration in experimental scrapie. Folia Neuropathol 45:170–178Google Scholar
- Yu FX, Lin SC, Morrison-Bogorad M, Atkinson MA, Yin HL (1993) Thymosin beta 10 and thymosin beta 4 are both actin monomer sequestering proteins. J Biol Chem 268:502–509Google Scholar
- Zhao RR, Xu F, Xu XC, Tan GJ, Liu LM, Wu N, Zhang WZ, Liu JX (2015) Effects of alpha-lipoic acid on spatial learning and memory, oxidative stress, and central cholinergic system in a rat model of vascular dementia. Neurosci Lett 587:113–119. https://doi.org/10.1016/j.neulet.2014.12.037 CrossRefGoogle Scholar