朊病毒疾病分为传染型、遗传型和随机偶发型，其中遗传型是由于朊蛋白突变而致。虽然朊病毒的构象还不明确，但是已知它不同于正常朊蛋白。通过对原核表达的突变型朊蛋白的研究表明这类蛋白的构象异于正常朊蛋白。在特定条件下，突变型朊蛋白会像朊病毒一样形成聚合体或具有蛋白水解酶K的抗性，虽然没有证据表明这些突变蛋白具有传染性。这些研究表明突变型朊蛋白的性质更接近于朊病毒。基于相关研究结果，我们认为突变型朊蛋白的致病机理是该类蛋白具有更开放的中段氨基酸序列和氨基末端，其结合受体的能力不同于正常的朊蛋白，因此引起了细胞的异常信号传导而导致神经细胞的缺陷。我们将从三个方面检验该假设，（1）突变型朊蛋白和正常朊蛋白是否存在构象的差别；（2）突变朊蛋白和正常朊蛋白结合受体的能力是否不同；（3）突变朊蛋白和正常朊蛋白引起的信号传导是否不一样。我们的研究将有助于理解由朊病毒引起的神经退行性疾病的机理。

Prion diseases are a group of neurodegenerative illnesses that can be infectious, inherited, and sporadic. Inherited prion diseases derived from mutations in the prion protein (PrP). The cellular mechanism of inherited prion diseases is not clear but it is likely that mutations altered the conformation of the proteins. In some experiments, PrP mutants behave like scrapie prion protein (PrPSc) to form aggregates and be resistant to PK digestion. However, no evidence shows that PrP mutants are infectious. Based on our previous results that prokaryotic expressed PrP mutants have a more exposed N-terminus and middle domain spanning from amino acids 109-136., and bind more GAGs, we hypothesize that conformational change and stronger GAGs binding might be the mechanism for this type of prion diseases. We would like to test our hypothesis from the following aspects: (1) Whether or not mutants and cellular prion protein (PrPC) are different in conformation. (2) Are there binding distinctness between mutants and PrPC to GAGs? (3) What differentiates the signal transduction pathways when mutants and PrPC bind GAGs? Our research will facilitate understanding of the mechanism of prion diseases.