Elucidating the cellular mechanisms of prion propagation and clearance for devisi

描述（由申请人提供）：阐明朊病毒传播和清除的细胞机制，为朊病毒疾病的干预设计新的靶点。越来越多的神经退行性疾病是由错误折叠蛋白聚集引起的，它们具有共同的病理生理机制。朊病毒疾病是典型的蛋白质错误折叠疾病，其发病机制仅与单细胞蛋白（PrPc）异常错误折叠有关。朊病毒疾病在这一群体中是独一无二的

DESCRIPTION (provided by applicant): Elucidating the cellular mechanisms of prion propagation and clearance for devising new targets for intervention in prion disease There are an increasing number of neurodegenerative disorders which result from the aggregation of misfolded proteins and which share patho-physiological mechanisms. Prion diseases are the prototypical protein misfolding diseases, and their pathogenesis is associated solely with aberrant misfolding of a single cellular protein (PrPc). Prion diseases are unique in this group as they are infectious disorders found in man and animals. Besides sporadic or genetic manifestation, they can be acquired by infection and transmitted between species, resulting in endemic or epidemic scenarios (e.g. BSE/vCJD and CWD). They can be controlled, but eradication is impossible. Therefore, it is mandatory to understand the molecular and cellular requirements for propagation and transmission of prions in order to device rational strategies for controlling these events. Advances in understanding prion patho-physiology will have major implications for other protein misfolding diseases, as it may help elucidate common cellular mechanisms. Such understanding is of fundamental scientific importance as neurodegenerative diseases represent one of the biggest health problems in our aging society, and uncovering molecular mechanisms of general validity is fundamental for the identification of new targets and development of rational therapies. The long-term goal of our group is to develop therapeutic and prophylactic anti-prion strategies. The overall objective we have is to study the cellular and molecular biology of prion infections and to use gained understanding for delineating novel targets for intervention. We have focused our attempts on two main strategies. One is the endogenous cellular clearance capacity for prions, the other one is to target the cellular isoform PrPc, which is a prerequisite for prion conversion and execution of neurodegeneration. It is our central hypothesis that it is feasible to interfere in prion propagation by increasing the cellular clearance for prions. Work in Aim 1 will substantiate our finding that prion clearance can be enhanced by compound-induced induction of autophagy, a basic cellular program for degradation and recycling. The proposed work intends to better understand the underlying molecular mechanisms and to validate the therapeutic and translational potential of this finding in vivo. Work in Aim 2 and 3 addresses cellular modifiers of prion formation. We have found that a basal level of autophagy is needed for establishing prion infection and we propose that autophagy represents the biological equivalent for the postulated disaggregase function in mammalian prion/prion-like biology. Our goal is to prove this at the cellular and molecular level. The rational for work in Aim 3 is that protein quality control mechanisms in the secretory pathway can directly influence prion conversion by determining on the quality of conversion substrates. We want to manipulate this by over-expressing folding and sorting proteins, in order to show that this represents a novel pathway counteracting prion propagation. Overall, our studies will provide mechanistic insights into basic cellular and molecular mechanisms which are relevant for neurodegenerative diseases and will result in novel targets for rational therapy against prion diseases and protein misfolding disorders.