Taking out the garbage:cathepsin D and calcineurin in neurodegeneration  

作　　者：Andreas Aufschnaiter Verena Kohler Sabrina Büttner 

机构地区：[1]Institute of Molecular Biosciences,University of Graz,HumboldtstraBe 50,8010 Graz,Austria [2]Department of Molecular Biosciences,The Wenner-Gren Institute,Stockholm University,Svante Arrheniusvag 20C,106 91 Stockholm,Sweden

出　　处：《Neural Regeneration Research》2017年第11期1776-1779,共4页中国神经再生研究（英文版）

基　　金：supported by the Austrian Science Fund FWF(No.P27183-B24);the Swedish Research Council Vetenskapsradet(No.2015-05468);Ake Wiberg Stiftelse(No.M16-0130);Carl Trygger Stiftlese(No.CTS16:85);Goljes Stiftelse(No.LA2016-0123)

摘　　要：Cellular homeostasis requires a tightly controlled balance between protein synthesis, folding and degradation. Especially long-lived, post-mitotic cells such as neurons depend on an efficient proteostasis system to maintain cellular health over decades. Thus, a functional decline of processes contributing to protein degradation such as autophagy and general lysosomal proteolytic capacity is connected to several age-associated neurodegenerative disorders, including Parkinson＇s, Alzheimer＇s and Huntington＇s diseases. These so called proteinopathies are characterized by the accumulation and misfolding of distinct proteins, subsequently driving cellular demise. We recently linked efficient lysosomal protein breakdown via the protease cathep- sin D to the Ca2＋/calmodulin-dependent phosphatase calcineurin. In a yeast model for Parkinson＇s disease, functional calcineurin was required for proper trafficking of cathepsin D to the lysosome and for recycling of its endosomal sorting receptor to allow further rounds of shuttling. Here, we discuss these findings in relation to present knowledge about the involvement of cathepsin D in proteinopathies in general and a possible connection between this protease, calcineurin signalling and endosomal sorting in particular. As dysregulation of Ca2＋ homeostasis as well as lysosomal impairment is connected to a plethora of neurode- generative disorders, this novel interplay might very well impact pathologies beyond Parkinson＇s disease.Cellular homeostasis requires a tightly controlled balance between protein synthesis, folding and degradation. Especially long-lived, post-mitotic cells such as neurons depend on an efficient proteostasis system to maintain cellular health over decades. Thus, a functional decline of processes contributing to protein degradation such as autophagy and general lysosomal proteolytic capacity is connected to several age-associated neurodegenerative disorders, including Parkinson＇s, Alzheimer＇s and Huntington＇s diseases. These so called proteinopathies are characterized by the accumulation and misfolding of distinct proteins, subsequently driving cellular demise. We recently linked efficient lysosomal protein breakdown via the protease cathep- sin D to the Ca2＋/calmodulin-dependent phosphatase calcineurin. In a yeast model for Parkinson＇s disease, functional calcineurin was required for proper trafficking of cathepsin D to the lysosome and for recycling of its endosomal sorting receptor to allow further rounds of shuttling. Here, we discuss these findings in relation to present knowledge about the involvement of cathepsin D in proteinopathies in general and a possible connection between this protease, calcineurin signalling and endosomal sorting in particular. As dysregulation of Ca2＋ homeostasis as well as lysosomal impairment is connected to a plethora of neurode- generative disorders, this novel interplay might very well impact pathologies beyond Parkinson＇s disease.

关 键 词：NEURODEGENERATION Parkinson’s disease Α-SYNUCLEIN cathepsin D CALCINEURIN RETROMER yeast LYSOSOME endosomal sorting 

分 类 号：R742.5[医药卫生—神经病学与精神病学]