Studies of Hereditary Neurological Disease: Disease Mechanisms

遗传性神经系统疾病的研究：疾病机制

• 批准号: 8746817
• 负责人: Kenneth Fischbeck
• 金额: $ 184.46万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8746817
• 关键词: Acute; Androgen Receptor; Animal Model; Attenuated; Binding Proteins; Blinded; Body Weight decreased; Caenorhabditis elegans; Cell Culture Techniques; Clinical; Clinical Trials; Cultured Cells; Denervation; Disease; Disease Progression; Genetic; Glutamine; Goals; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Histones; Human; In Vitro; Inherited; Injection of therapeutic agent; Insulin-Like Growth Factor I; Intervention; Intraperitoneal Injections; Investigation; Kennedy Syndrome; Link; Mediating; Mind; Motor; Mus; Muscle; Muscle Proteins; Muscular Atrophy; Myogenin; Neuromuscular Diseases; Neuromuscular Junction; Onset of illness; Orthologous Gene; Pathology; Pathway interactions; Patients; Performance; Peripheral; Phenotype; Phosphorylation; Proteasome Inhibition; Protein Deficiency; Protein Isoforms; Proteins; Randomized; Receptor Aggregation; Recombinant IGF-I; Recombinants; Reporting; Research; Ring Finger Domain; Spinal Cord; Spinal Muscular Atrophy; System; Therapeutic Intervention; Tissues; Toxic effect; Transgenic Mice; Ubiquitin; effective therapy; human HDAC4 protein; improved; knock-down; motor function improvement; mouse model; multicatalytic endopeptidase complex; mutant; nervous system disorder; neuromuscular function; new therapeutic target; overexpression; polyglutamine; programs; spinal and bulbar muscular atrophy; therapeutic target; ubiquitin-protein ligase

The purpose of this research program is to investigate the mechanisms of hereditary neurological diseases, with the ultimate intent of developing effective treatments for these disorders. Recently, the research has focused on two specific neuromuscular diseases: autosomal recessive spinal muscular atrophy (SMA) due to deficiency of the protein SMN, X-linked spinal and bulbar muscular atrophy (SBMA) due to polyglutamine expansion in the androgen receptor. Specific research accomplishments reported recently include the following: (1) Identification of an E3 ligase, mind bomb 1 (Mib1), responsible for the degradation of SMN protein. SMN is ubiquitinated and degraded through the ubiquitin proteasome system (UPS). We have previously shown that proteasome inhibition improves motor function, and reduces spinal cord, muscle, and neuromuscular junction pathology of spinal muscular atrophy mice, suggesting that the UPS is a potential therapeutic target for this disease. While inhibiting the proteasome provides proof of concept that the UPS can be targeted to increase SMN protein levels, specific targets in this pathway may be more efficacious and less toxic. In this study, we show that the E3 ubiquitin ligase, Mib1, interacts with and ubiquitinates SMN and facilitates its degradation. Knocking down Mib1 levels increases SMN protein levels in cultured cells. In addition, knocking down the Mib1 ortholog improves neuromuscular function in Caenorhabditis elegans deficient in SMN. These findings demonstrate that Mib1 ubiquitinates and catalyzes the degradation of SMN, and thus represents a novel therapeutic target for spinal muscular atrophy. (2) Characterization of the effects of histone deacetylase inhibition in SMA muscle. During muscle atrophy, the E3 ligase atrogenes, atrogin-1 and muscle ring finger 1 (MuRF1), mediate muscle protein breakdown through the ubiquitin proteasome system. Atrogene expression can be induced by various upstream regulators. During acute denervation, they are activated by myogenin, which is in turn regulated by histone deacetylases 4 and 5. We showed that atrogenes are induced in SMA model mice and in SMA patient muscle in association with increased myogenin and histone deacetylase-4 (HDAC4) expression. This activation during both acute denervation and SMA disease progression is suppressed by treatment with a histone deacetylase inhibitor; however, this treatment has no effect when atrogene induction occurs independently of myogenin. These results indicate that myogenin-dependent atrogene induction is amenable to pharmacological intervention with histone deacetylase inhibitors and help to explain the beneficial effects of these agents on SMA and other denervating diseases. (3) Characterization of the effects of IGF-1 in an animal model of SBMA. Our recent studies have demonstrated that IGF-1 reduces the mutant androgen receptor toxicity through activation of Akt in vitro, and spinal and bulbar muscular atrophy transgenic mice that also overexpress a non-circulating muscle isoform of IGF-1 have a less severe phenotype. Here we sought to establish the efficacy of daily intraperitoneal injections of mecasermin rinfabate, recombinant human IGF-1 and IGF-1 binding protein 3, in a transgenic mouse model expressing the mutant androgen receptor with an expanded 97 glutamine tract. The study was done in a controlled, randomized, blinded fashion, and in order to reflect the clinical settings the injections were started after the onset of disease manifestations. The treatment resulted in increased Akt phosphorylation and reduced mutant androgen receptor aggregation in muscle. In comparison to vehicle-treated controls, IGF-1 treated transgenic mice showed improved motor performance, attenuated weight loss, and increased survival. Our results suggest that peripheral tissue can be targeted to improve the spinal and bulbar muscular atrophy phenotype and indicate that IGF-1 warrants further investigation in clinical trials as a potential treatment for this disease.

这项研究计划的目的是研究遗传性神经系统疾病的机制，最终目的是为这些疾病开发有效的治疗方法。最近，研究集中在两种特定的神经肌肉疾病：常染色体隐性脊髓性肌萎缩症（SMA），由于蛋白质SMN的缺乏，x -连锁脊髓和球性肌萎缩症（SBMA），由于雄激素受体中聚谷氨酰胺的扩增。最近报告的具体研究成果包括：