Increased BACE1 mRNA and noncoding BACE1-antisense transcript in sporadic inclusion-body myositis muscle fibers--possibly caused by endoplasmic reticulum stress.
Increased BACE1 mRNA and noncoding BACE1-antisense transcript in sporadic inclusion-body myositis muscle fibers--possibly caused by endoplasmic reticulum stress.
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DOI：
10.1016/j.neulet.2010.03.023
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发表时间：
2010-05-03
影响因子：
2.5
通讯作者：
Askanas V
中科院分区：
文献类型：
--
作者：
Nogalska A;Engel WK;Askanas V
散发性包涵体肌炎是老年人最常见的肌肉疾病。它的肌肉纤维表型与阿尔茨海默病(AD)脑有几个分子上的相似之处，包括AβPP增加，淀粉样蛋白(Aβ，Aβ)积聚，以及BACE1蛋白增加。Aβ42在AD大脑和S-ibm纤维中显著增加，其寡聚体对这两个组织可能是有毒的--因此，最大限度地减少Aβ42的产生可以成为两个组织的治疗目标。S-肠易激综合征的发病机制尚不清楚，包括BACE1蛋白升高的机制。BACE1是从AβPP的Aβ42和Aβ40中产生的一种必不可少的酶，这两种酶被认为对S-ibm肌肉纤维中的蛋白质是有害的。最近发现的新的非编码BACE1-反义(BACE1-AS)基因在AD脑中表达增加，并且增加了BACE1mRNA和BACE1蛋白。我们用实时定量聚合酶链式反应研究了BACE1-AS和BACE1转录本：a)在10例S-IBM和10例年龄匹配的正常肌肉组织中；以及b)在我们建立的ER-Stress-Human-Muscle-Culture IBM模型中，我们先前证实了BACE1蛋白的增加。我们的研究首次证明：a)在S-IBM肌肉组织中，BACE1-AS和BACE1的转录本显著增加，提示它们的表达增加可能是导致BACE1蛋白表达增加的原因；b)实验性内质网应激显著增加BACE1-AS和BACE1的转录本，提示内质网应激可能参与了S-IBM肌肉中BACE1-AS和BACE1的诱导。因此，假设不会损害BACE1的任何正常细胞功能，通过有针对性地下调其调控的BACE1-AS或减少内质网应激来降低BACE1可能是S-IBM的治疗策略。
Sporadic inclusion-body myositis (s-IBM) is the most common muscle disease of older persons. Its muscle-fiber phenotype shares several molecular similarities with Alzheimer-disease (AD) brain, including increased AβPP, accumulation of amyloid-β (Aβ), and increased BACE1 protein. Aβ42 is prominently increased in AD brain and within s-IBM fibers, and its oligomers are putatively toxic to both tissues -- accordingly, minimizing Aβ42 production can be a therapeutic objective in both tissues. The pathogenic development of s-IBM is unknown, including the mechanisms of BACE1 protein increase. BACE1 is an enzyme essential for production from AβPP of Aβ42 and Aβ40, which are proposed to be detrimental within s-IBM muscle fibers. Novel noncoding BACE1-antisense (BACE1-AS) was recently shown a)to be increased in AD brain, and b) to increase BACE1 mRNA and BACE1 protein. We studied BACE1-AS and BACE1 transcripts by real-time PCR a) in 10 s-IBM and 10 age-matched normal muscle biopsies; and b) in our established ER-Stress-Human-Muscle-Culture IBM Model, in which we previously demonstrated increased BACE1 protein. Our study demonstrated for the first time that a) in s-IBM biopsies BACE1-AS and BACE1 transcripts were significantly increased, suggesting that their increased expression can be responsible for the increase of BACE1 protein; and b) experimental induction of ER stress significantly increased both BACE1-AS and BACE1 transcripts, suggesting that ER stress can participate in their induction in s-IBM muscle. Accordingly, decreasing BACE1 through a targeted downregulation of its regulatory BACE1-AS, or reducing ER stress, might be therapeutic strategies in s-IBM, assuming that it would not impair any normal cellular functions of BACE1.
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