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Cellular events in heritable peripheral neuropathies

遗传性周围神经病的细胞事件

基本信息

批准号：
8462693
负责人：
LUCIA NOTTERPEK
金额：
$ 29.22万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-15 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8462693
关键词：
Abbreviations Accounting Adult Aftercare Amino Acid Substitution Attenuated Autophagocytosis Biopsy Cell physiology Cells Charcot-Marie-Tooth Disease Cultured Cells Cytoplasm Cytosol Diet Disease Disease model Endoplasmic Reticulum Degradation Pathway Enhancers Equilibrium Event Excision Fasting Geldanamycin Genes Grant HSF1 Heat shock proteins Heat-Shock Proteins 90 Heat-Shock Response Integral Membrane Protein Investigation Modeling Molecular Chaperones Morphology Mus Muscular Atrophy Mutate Myelin Myelin Basic Proteins Myelin P0 Protein Myelin Proteins Neonatal Nerve Nerve Degeneration Nerve Tissue Neuropathy Pathogenesis Pathway interactions Patients Performance Peripheral Peripheral Nerves Peripheral Nervous System Peripheral Nervous System Diseases Phenotype Process Production Proteins Proteolysis Recruitment Activity Sampling Schwann Cells Sirolimus Spinal Ganglia Staging Starvation Syndrome System Testing Therapeutic Therapeutic Intervention Treatment outcome Ubiquitin Work abstracting advanced disease base efficacy testing functional disability heat-shock factor 1 hereditary neuropathy improved in vivo inhibitor/antagonist mouse model multicatalytic endopeptidase complex mutant myelination neuromuscular function preclinical study protein aggregate protein degradation protein expression protein transport research study response small molecule success

项目摘要

Abstract Heritable demyelinating neuropathies, including Charcot-Marie-Tooth disease type 1A (CMT1A), account for a significant portion of peripheral nerve disorders leading to muscle atrophy and functional impairment. Peripheral myelin protein 22 (PMP22) is a hydrophobic integral membrane protein within Schwann cells, whose abnormal expression is associated with the majority of CMT1A cases. In most patients with demyelinating neuropathy, the PMP22 gene is duplicated, while in a smaller fraction of CMT1A and in Dejerine-Sottas Syndrome, single amino acid substitutions in PMP22 are present. Studies of nerve biopsies from neuropathic patients revealed abnormal retention of PMP22 within the Schwann cell cytosol, and the lack of correct myelin protein expression. To gain understanding into the subcellular pathogenesis of PMP22- associated neuropathies, we have characterized the posttranslational processing of PMP22 and found slowed degradation and abnormal intracellular accumulation of the protein within Schwann cells from neuropathic mice, including the point mutant Trembler J and the PMP22 overexpressor models. Since cytosolic PMP22 is only detected in nerve tissue from neuropathic and not normal mice, the abnormal intracellular accumulation of PMP22 likely contributes to the disease pathogenesis. Indeed, upon overwhelming the ubiquitin-proteasome pathway, cytosolic aggregates of PMP22 form and recruit essential Schwann cell molecules, including chaperones and myelin proteins, which alter the protein balance of the cell. Under permissive conditions, Schwann cells isolated from neonatal nerves have the ability to clear these abnormal cytosolic protein aggregates by a mechanism that is assisted by chaperones and autophagy. During the current cycle of this project, we stimulated the chaperone and autophagic responses within samples from Trembler J and PMP22 overexpressor mice, and found that the abnormal cytosolic aggregation of PMP22 can be suppressed and myelin production improved. Furthermore, we have shown that dietary stimulation of these pathways has proven beneficial to these neuropathic mice. The success of these proof-of-principle experiments sets the stage to move forward with specific pharmacologic treatment paradigms in neuropathic mice, and evaluate treatment outcome on neuromuscular function, nerve morphology and associated subcellular mechanisms. The overall aim of this project is to determine if pharmacologic enhancement of chaperones and autophagic protein degradation can slow or halt the progression of the neuropathy in young mice, and to investigate the response of samples from advanced disease stages to this approach. We will use pharmacologically characterized, known small molecules to stimulate the chaperone and autophagy pathways in young neuropathic mice and in ex vivo samples from advanced disease state mice. These studies will determine if improving the subcellular processing of PMP22 by stimulation of protein homeostatic mechanisms within Schwann cells could provide a viable approach for therapy in CMT1A and related neuropathies.

摘要遗传性脱髓鞘神经病，包括腓骨肌萎缩症1A型（CMT1A），导致肌肉萎缩和功能障碍的外周神经疾病的重要部分损伤外周髓磷脂蛋白22（Peripheral myelin protein 22，PMP 22）是雪旺氏细胞内的一种疏水性膜蛋白细胞，其异常表达与大多数CMT1A病例相关。在大多数患有在脱髓鞘性神经病中，PMP 22基因是重复的，而在CMT1A的较小部分中， Dejerine-Sottas综合征，PMP 22中存在单个氨基酸取代。神经活检研究神经病患者的研究显示，PMP22异常滞留在雪旺细胞胞质溶胶中，正确的髓鞘蛋白表达。为了了解PMP22 - 1的亚细胞发病机制，相关的神经病变，我们的特点是翻译后加工的PMP 22，并发现减缓神经病理性雪旺氏细胞内蛋白质的降解和异常细胞内积累小鼠，包括点突变体Trembler J和PMP 22过表达模型。由于胞质PMP22是仅在来自神经病小鼠而非正常小鼠的神经组织中检测到， PMP22可能有助于疾病的发病机制。事实上，在压倒泛素-蛋白酶体之后，在PMP22通路中，PMP22的胞质聚集体形成并募集必需的雪旺细胞分子，包括分子伴侣和髓磷脂蛋白，它们改变细胞的蛋白质平衡。在允许的条件下，从新生神经中分离的雪旺细胞具有清除这些异常胞浆蛋白的能力通过分子伴侣和自噬辅助的机制聚集。在当前的周期中，项目中，我们刺激了来自Trembler J和PMP 22的样品中的伴侣蛋白和自噬反应。过表达小鼠，并发现可以抑制PMP22的异常胞质聚集，髓磷脂的产生得到改善。此外，我们已经表明，饮食刺激这些途径，被证明对这些神经病小鼠有益。这些原理验证实验的成功，在神经病小鼠中使用特定的药理学治疗范例，并评估神经肌肉功能、神经形态学和相关亚细胞机制的治疗结果。该项目的总体目标是确定是否有分子伴侣和自噬的药理学增强，蛋白质降解可以减缓或停止年轻小鼠神经病变的进展，来自晚期疾病阶段的样品对这种方法的反应。我们将使用特征，已知的小分子刺激伴侣和自噬途径，在年轻的神经病小鼠和来自晚期疾病状态小鼠的离体样品。这些研究将确定，通过刺激细胞内的蛋白质稳态机制来改善PMP 22的亚细胞加工雪旺细胞可以为CMT1A和相关神经病变的治疗提供一种可行的方法。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Long-term analyses of innervation and neuromuscular integrity in the Trembler-J mouse model of Charcot-Marie-Tooth disease.

对腓骨肌萎缩症 Trembler-J 小鼠模型的神经支配和神经肌肉完整性进行长期分析。

DOI：
10.1097/nen.0b013e3182a5f96e
发表时间：
2013
期刊：
Journal of neuropathology and experimental neurology
影响因子：
3.2
作者：
Nicks,JessicaRenee;Lee,Sooyeon;Kostamo,KathryneAnn;Harris,AndrewBenford;Sookdeo,AmandaM;Notterpek,Lucia
通讯作者：
Notterpek,Lucia

Liposomes to target peripheral neurons and Schwann cells.