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Anti-fibrotic approach and reactivation of neurogenesis by targeting the TGF-ß System (P5.021)

Neurology(2018)

引用 23|浏览13
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摘要
Objective: To test the hypothesis, whether TGF-s receptor II (TGFRII) specific antisense-oligonucleotide (ASO)-mediated inhibition of TGF-s signaling will rescue adult neurogenesis and oppose neurodegeneration as studied in human neuronal progenitor cells (ReNcell CX®, Millipore). Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no effective treatment so far. Actual research is elucidating molecular pathogenesis of this fatal disease. Most probably ALS patients have multifactorial mechanisms causing several additional hits. It is known that TGF-s is often elevated during pathogenesis of different disorders including neurodegenerative diseases or fibrosis. Often, these TGF-smediated alterations correlate with disease progression. ALS patients show high levels of circulating and CNS-tissue TGF-s that contribute to arrested neurogenesis. In addition, TGF-s is related to pathogenic modifications of extracellular matrix (ECM) and the actin-cytoskeleton. Thus, it is tempting to analyze if an (ASO)-mediated inhibition of TGF-s signaling has effects on stem cell proliferation and fibrotic processes in neuronal precursor cells. Design/Methods: To analyze an effective target downregulation TGFRII levels were determined. Inhibition of TGF-s signaling was confirmed by an evaluation of CTGF and pSmad2 levels. Expression of FN, ColIV and the modulation of actin-cytoskeleton (Phalloidin) was examined to clarify an involvement in anti-fibrotic effects in neuronal degeneration. In addition, proliferation of neuronal precursor cells and neurogenesis marker DCX were observed to examine if targeting the TGF-s system leads to a neuronal regeneration. Data were obtained by quantitative real-time RT-PCR, immunoblotting, immunocytochemistry and cell counting. Results: Results indicate that blocking cellular TGF-s signaling by selective ASO leads to reduction of fibrotic deposition and a re-modulation of actin-cytoskeleton. Furthermore, the application of ASO lead to a reactivation of adult neurogenesis in neuronal precursor cells and to an increase of DCX, a marker for neurogenesis. Conclusions: Targeting the TGF-s system by TGFRII-specific oligonucleotide is a promising therapeutic intervention to counteract neuronal degeneration in ALS. Study Supported by: GoBio Disclosure: Dr. Kuespert has nothing to disclose. Dr. Poellmann has nothing to disclose. Dr. Heydn has nothing to disclose. Dr. Zitzelsperger has nothing to disclose. Dr. Peters has nothing to disclose. Dr. Meyer has nothing to disclose. Dr. Bruun has nothing to disclose. Dr. Aigner has nothing to disclose. Dr. Bogdahn has nothing to disclose.
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关键词
neurogenesis,anti-fibrotic
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