Multiple functions of precursor BDNF to CNS neurons: negative regulation of neurite growth, spine formation and cell survival.
Multiple functions of precursor BDNF to CNS neurons: negative regulation of neurite growth, spine formation and cell survival.
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DOI：
10.1186/1756-6606-2-27
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发表时间：
2009-08-13
期刊：
影响因子：
3.6
通讯作者：
Kojima M
中科院分区：
文献类型：
--
作者：
Koshimizu H;Kiyosue K;Hara T;Hazama S;Suzuki S;Uegaki K;Nagappan G;Zaitsev E;Hirokawa T;Tatsu Y;Ogura A;Lu B;Kojima M
前神经营养因子和成熟神经营养因子分别通过p75神经营养因子受体（p75 NTR）和Trk酪氨酸激酶受体引起相反的作用;然而，前神经营养因子在CNS中的分子作用尚未完全理解。基于人脑源性神经营养因子（BDNF）基因的两个罕见的单核苷酸多态性（SNP），我们产生了R125 M-、R127 L-和R125 M/R127 L-BDNF，它们在BDNF的原结构域和成熟结构域之间的切割位点附近具有氨基酸取代。蛋白质印迹分析表明，这些BDNF变异体被不良切割，导致主要分泌的proBDNF。使用这些抗切割的proBDNF（CR-proBDNF）变体，检测proBDNF对CNS神经元的分子和细胞作用。首先，CR-proBDNF在培养的海马神经元中显示正常的细胞内分布和分泌，表明抑制proBDNF切割不影响BDNF的细胞内运输和分泌。其次，我们纯化重组CR-proBDNF，并使用培养的CNS神经元测试其生物学效应。用CR-proBDNF处理引起培养的小脑颗粒神经元（CGNs）凋亡，而用成熟BDNF（matBDNF）处理促进细胞存活。第三，我们使用超过2周的基底前脑胆碱能神经元（BFCNs）和海马神经元培养物研究了CR-proBDNF对神经元形态的影响。有趣的是，与增加胆碱能纤维和海马树突棘的数量的matBDNF的作用形成鲜明对比，CR-proBDNF显著减少胆碱能纤维和海马树突棘的数量，而不影响这些神经元的存活。这些结果表明，proBDNF在不同的CNS神经元群体中具有不同的功能，并且可能负责脑中特定的生理细胞过程。
Proneurotrophins and mature neurotrophins elicit opposite effects via the p75 neurotrophin receptor (p75NTR) and Trk tyrosine kinase receptors, respectively; however the molecular roles of proneurotrophins in the CNS are not fully understood. Based on two rare single nucleotide polymorphisms (SNPs) of the human brain-derived neurotrophic factor (BDNF) gene, we generated R125M-, R127L- and R125M/R127L-BDNF, which have amino acid substitution(s) near the cleavage site between the pro- and mature-domain of BDNF. Western blot analyses demonstrated that these BDNF variants are poorly cleaved and result in the predominant secretion of proBDNF. Using these cleavage-resistant proBDNF (CR-proBDNF) variants, the molecular and cellular roles of proBDNF on the CNS neurons were examined. First, CR-proBDNF showed normal intracellular distribution and secretion in cultured hippocampal neurons, suggesting that inhibition of proBDNF cleavage does not affect intracellular transportation and secretion of BDNF. Second, we purified recombinant CR-proBDNF and tested its biological effects using cultured CNS neurons. Treatment with CR-proBDNF elicited apoptosis of cultured cerebellar granule neurons (CGNs), while treatment with mature BDNF (matBDNF) promoted cell survival. Third, we examined the effects of CR-proBDNF on neuronal morphology using more than 2-week cultures of basal forebrain cholinergic neurons (BFCNs) and hippocampal neurons. Interestingly, in marked contrast to the action of matBDNF, which increased the number of cholinergic fibers and hippocampal dendritic spines, CR-proBDNF dramatically reduced the number of cholinergic fibers and hippocampal dendritic spines, without affecting the survival of these neurons. These results suggest that proBDNF has distinct functions in different populations of CNS neurons and might be responsible for specific physiological cellular processes in the brain.
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影响因子：
16.2
作者：
ALDERSON, RF;ALTERMAN, AL;LINDSAY, RM
通讯作者：
LINDSAY, RM
影响因子：
25
作者：
Matsumoto, Tomoya;Rauskolb, Stefanie;Barde, Yves-Alain
通讯作者：
Barde, Yves-Alain
DOI：
10.1073/pnas.0807322106
发表时间：
2009-01-27
影响因子：
11.1
作者：
Nagappan, Guhan;Zaitsev, Eugene;Lu, Bai
通讯作者：
Lu, Bai
影响因子：
16.2
作者：
Beattie, MS;Harrington, AW;Yoon, SO
通讯作者：
Yoon, SO
prion蛋白通过抑制NMDA受体减轻兴奋性毒性。
影响因子：
7.8
作者：
Khosravani, Houman;Zhang, Yunfeng;Tsutsui, Shigeki;Hameed, Shahid;Altier, Christophe;Hamid, Jawed;Chen, Lina;Villemaire, Michelle;Ali, Zenobia;Jirik, Frank R.;Zamponi, Gerald W.
通讯作者：
Zamponi, Gerald W.