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[7.14]NS Forum No.272-Motor neuron disease: Is there a cure?
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| 2016-07-13 | 浏览次数: | 文章来源: | 【大 中 小】 |
中科院纳米生物效应与安全性重点实验室
纳米技术论坛 (NS Forum No.272)
第272期学术报告会通知
报告人：Prof. Jiming Kong University of Manitoba
题 目：Motor neuron disease: Is there a cure?
时 间：2016年7月14日（星期四） 下午14:30
地 点：国家纳米科学中心, 南楼五层会议室
主持人：梁兴杰 研究员
报告摘要 :Over the past two decades, a major breakthrough in ALS research is the discovery that mutations in the gene Cu/Zn superoxide dismutase type-1 (SOD1) are a cause of familial ALS. Familial ALS (FALS)-linked SOD1 variants are readily susceptible to posttranslational modifications, and subsequently become misfolded. Failure in degradation of unfavorable SOD1 with ubiquitin and/or autophagy-proteasome system leads to accumulation of SOD1 aggregates and triggers a toxic cascade leading to motor neuron degeneration. Notably, wild type SOD1, when modified post-translationally, undergoes aberrant conformational changes and acquires the same toxic functions as FALS-associated SOD1 variants. Thus, misfolded SOD1 is a common toxic factor to a subset of both familial and sporadic ALS. Selective clearance of misfolded SOD1 is therefore a rational approach towards developing effective therapies for ALS. Here we report a peptide-direct protein knockdown system that rapidly and selectively degrades misfolded SOD1 through a chaperone-mediated autophagy pathway. The peptide system consists of a cell membrane–penetrating domain that allows the peptide to bypass the blood-brain barrier and plasma membrane following peripheral delivery, a cytosolic carboxyl terminal region of the Derlin-1 CT4motif that selectively binds to misfolded SOD1, and achaperone-mediated autophagy-targeting motif (CTM) that directs the peptide-protein complex for lysosomal degradation. Co-expression of the peptide with either the G93A or the G37R mutations of human SOD1 shows a significant reduction of the levels of both G93A and G37R, but not the wild type SOD1 in the control group. Inducing misfolding of human SOD1 by serum deprivation or increasing lysosomal activity robustly increases the knockdown efficiency of misfolded SOD1. The knocking down function of the peptide can be completely abolished when either the CT4 domain or the CTM domain is mutated. Our data so far shows that the peptide system effectively knocks down misfolded SOD1 in a dose-, time- and lysosomal activity–dependent manner. We are currently testing the knockdown efficiency and specificity of the peptide system on misfolded SOD1 in animal models of ALS. We are hopeful that thepeptide-direct protein knockdown systemcan be potentially developed into a cure for ALS. |
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