Cysteine-string Protein and Neurodegeneration

了解神经退行性疾病的病因和开发潜力的必要性 随着预期寿命的延长，治疗也在增加。神经元蜡样脂褐质沉积症（NCL;也 称为Batten病）包括一组14种单基因神经变性疾病， 溶酶体病理学（CLN 1 -14）。NCL通常是由于基因的隐性突变， 溶酶体功能或ER-溶酶体运输，但有一个非典型例外：显性遗传的NCL CLN 4，由突触囊泡（SV）蛋白CSPα突变引起。通常，CSPα是关键的 以维持突触功能并防止活动依赖性神经变性。它还调解了 通过非常规分泌途径清除聚集蛋白如TDP-43或α-突触核蛋白。 关于CLN 4疾病的病因学知之甚少，除了CLN 4引起的生物化学证据之外。 突变诱导泛素化CSPα寡聚体/聚集体的形成。是否以及如何 寡聚体或单体蛋白质导致溶酶体衰竭、神经变性和过早死亡 仍然是个谜我们已经建立了第一个CLN 4的动物模型， 人CSPα（hCSPα）或果蝇CSP（dCSP）。这两种模型都概括了 CLN 4死后大脑的生化病理学。进一步的分析显示， CLN 4突变CSP和前溶酶体衰竭。出乎意料的是，我们还发现， 等位基因作为功能突变的超形态获得，诱导CSP寡聚化， 衰竭，神经退化和致命性 我们认为，CLN 4的多态性突变增加了CSP的一些或一个蛋白的亲和力， 相互作用导致疾病。除了CSP的过度二聚导致低聚之外， CLN 4突变增加CSP与突触定位棕榈酰转移酶Hip 14的相互作用 可能导致前溶酶体衰竭最后，增加CSP与Hsc 70在核内体上的相互作用， 注定形成多泡体的细胞可能会干扰它们的加工、分选和/或运输。我们 我建议通过遗传学方法来测试这些可能性，以更好地理解这两种机制， CSP的正常神经保护作用的基础，以及高形态CLN 4的机制 导致蛋白质聚集、溶酶体衰竭、神经变性和过早死亡的突变。 揭示CLN 4的潜在机制可能会为未来的治疗发展提供信息。 干预措施。此外，更好地了解CSP的神经保护作用对于各种疾病的发生也很重要。 其他神经退行性疾病，可以通过CSP清除错误折叠的蛋白质来减弱。

The necessity of understanding causes of neurodegenerative diseases and developing potential treatments is increasing as life expectancy is extending. Neuronal ceroid lipofuscinoses (NCLs; also known as Batten disease) comprise a group of 14 monogenic neurodegenerative diseases with lysosomal pathology (CLN1-14). NCLs are typically due to recessive mutations in genes that mediate lysosomal function or ER-lysosomal trafficking with one atypical exception: the dominantly inherited NCL CLN4, which is caused by mutations in the synaptic vesicle (SV) protein CSPα. Normally, CSPα is critical to maintain synaptic function and prevent activity-dependent neurodegeneration. It also mediates the clearance of aggregating proteins like TDP-43 or α-synuclein by unconventional secretion pathways. Little is known about CLN4 disease etiology besides biochemical evidence that CLN4-causing mutations induce the formation of ubiquitinated CSPα oligomers/aggregates. Whether and how the oligomeric or monomeric protein causes lysosomal failure, neurodegeneration, and premature death remains enigmatic. We have established the first animal models of CLN4 by expressing disease-causing human CSPα (hCSPα) or fly CSP (dCSP) in Drosophila neurons. Both models recapitulate the biochemical pathology of CLN4 post-mortem brains. Further analysis revealed a novel link between CLN4 mutant CSP and prelysosomal failure. Unexpectedly, we also found that the dominant CLN4 alleles act as hypermorphic gain of function mutations inducing the oligomerization of CSP, prelysosomal failure, neurodegeneration, and lethality. We suggest that hypermorphic CLN4 mutations increase the affinity for some or one of CSP’s protein interaction causing disease. Next to an exaggerated dimerization of CSP leading to oligomerization, CLN4 mutations increase interactions of CSP with the synaptically localized palmitoyl-transferase Hip14 that could lead to prelysosomal failure. Finally, increased interactions of CSP with Hsc70 on endosomes destined to form multivesicular bodies may interfere with their processing, sorting and/or trafficking. We propose to test these possibilities by genetic approaches to better understand both the mechanisms underlying CSP’s normal neuroprotective role, and the mechanisms underlying the hypermorphic CLN4 mutations causing protein aggregation, lysosomal failure, neurodegeneration, and premature death. Uncovering mechanisms underlying CLN4 may inform the future development of therapeutic interventions. In addition, a better understanding of CSP’s neuroprotective role is important for various other neurodegenerative diseases that may be attenuated by CSP’s clearance of misfolded proteins.