Wojcik Slawomir, Engel W King, Yan Riqiang, McFerrin Janis, Askanas Valerie
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, 637 S. Lucas Ave, Los Angeles, CA 90017-1912, USA.
Acta Neuropathol. 2007 Nov;114(5):517-26. doi: 10.1007/s00401-007-0281-y. Epub 2007 Aug 31.
Increased amyloid-beta precursor protein (A beta PP) and amyloid-beta (A beta) accumulation appear to be upstream steps in the pathogenesis of sporadic inclusion-body myositis (s-IBM). BACE1, participating in A beta production is also increased in s-IBM muscle fibers. Nogo-B and Nogo-A belong to a family of integral membrane reticulons, and Nogo-B binding to BACE1 blocks BACE1 access to A beta PP, decreasing A beta production. We studied Nogo-B and Nogo-A in s-IBM muscle and in our IBM muscle culture models, based on A beta PP-overexpression or ER-stress-induction in cultured human muscle fibers (CHMFs). We report that: (1) in biopsied s-IBM fibers, Nogo-B is increased, accumulates in aggregates, is immuno-co-localized with BACE1, and binds to BACE1; Nogo-A is undetectable. (2) In CHMFs, (a) A beta PP overexpression increases Nogo-B, Nogo-A, and BACE1, (b) ER stress increases BACE1 but decreases Nogo-B and Nogo-A, (c) Nogo-B and Nogo-A associate with BACE1. Accordingly, two novel mechanisms, A beta PP overexpression and ER stress, are involved in Nogo-B and Nogo-A expression in human muscle. We propose that in s-IBM muscle the Nogo-B increase may represent an attempt by muscle fiber to decrease A beta production. However, the increase of Nogo-B seems insufficient because A beta continues to accumulate and the disease progresses. We propose that manipulations, which increase Nogo-B in s-IBM muscle might offer a new therapeutic opportunity.
淀粉样前体蛋白（AβPP）和淀粉样β蛋白（Aβ）积累增加似乎是散发性包涵体肌炎（s-IBM）发病机制中的上游步骤。参与Aβ产生的β-分泌酶1（BACE1）在s-IBM肌纤维中也增加。Nogo-B和Nogo-A属于整合膜网织蛋白家族，Nogo-B与BACE1结合可阻止BACE1接触AβPP，从而减少Aβ产生。我们基于培养的人肌纤维（CHMFs）中AβPP过表达或内质网应激诱导，研究了s-IBM肌肉以及我们的IBM肌肉培养模型中的Nogo-B和Nogo-A。我们报告如下：（1）在活检的s-IBM纤维中，Nogo-B增加，聚集形成聚集体，与BACE1免疫共定位，并与BACE１结合；未检测到Nogo-A。（2）在CHMFs中，（a）AβPP过表达增加Nogo-B、Nogo-A和BACE1，（b）内质网应激增加BACE1，但减少Nogo-B和Nogo-A，（c）Nogo-B和Nogo-A与BACE1相关联。因此，两种新机制，即AβPP过表达和内质网应激，参与了人肌肉中Nogo-B和Nogo-A的表达。我们提出，在s-IBM肌肉中Nogo-B增加可能代表肌纤维试图减少Aβ产生。然而，Nogo-B的增加似乎并不充分，因为Aβ继续积累且疾病仍在进展。我们提出，增加s-IBM肌肉中Nogo-B的操作可能提供新的治疗机会。
