{"id":682,"date":"2024-10-16T22:09:29","date_gmt":"2024-10-16T22:09:29","guid":{"rendered":"http:\/\/wmtc2006.com\/?p=682"},"modified":"2024-10-16T22:09:29","modified_gmt":"2024-10-16T22:09:29","slug":"pathologically-synuclein-mutations-and-synuclein-overexpression-cause-parkinsons-disease-and-aggregates-of-synuclein-are-found-as-lewy-bodies-in-multiple-neurodegenerative-disorders-s","status":"publish","type":"post","link":"https:\/\/wmtc2006.com\/?p=682","title":{"rendered":"\ufeffPathologically, -synuclein mutations and -synuclein overexpression cause Parkinson&#8217;s disease, and aggregates of -synuclein are found as Lewy bodies in multiple neurodegenerative disorders (synucleinopathies)"},"content":{"rendered":"<p>\ufeffPathologically, -synuclein mutations and -synuclein overexpression cause Parkinson&#8217;s disease, and aggregates of -synuclein are found as Lewy bodies in multiple neurodegenerative disorders (synucleinopathies). for its physiological function as SNARE-complex chaperone, but that these sequences were not essential for its neuropathological effects. In contrast, point mutations in the central region of -synuclein, referred to as nonamyloid component (residues 61C95), as well as point mutations linked to Parkinson&#8217;s disease (A30P, E46K, and A53T) increased the neurotoxicity of -synuclein but did not affect its physiological function in SNARE-complex assembly. Thus, our data show that the physiological function of -synuclein, although protective of neurodegeneration in some contexts, is fundamentally distinct from its neuropathological effects, thereby dissociating the two activities of -synuclein. Introduction -Synuclein is a small abundant neuronal protein that is natively unstructured, but folds into amphipathic -helices in the presence of negatively charged lipids (Maroteaux et al., 1988; Perrin et al., 2000), binds to synaptobrevin-2\/VAMP2 (Burr et al., 2010), and localizes to synaptic vesicles in nerve terminals (Iwai et al., 1995). and in cultured cells and neurons, -synuclein promotes SNARE-complex assembly (Burr et al., 2010). Three synuclein genes are expressed in mammals that encode -synuclein, -synuclein, and -synuclein. \/\/-Synuclein triple knock-out (KO) mice develop progressive neuropathology and motor impairments, die prematurely, and exhibit impaired SNARE-complex assembly, which is consistent with the idea that -synuclein functions as a SNARE-complex chaperone (Burr et al., 2010; Greten-Harrison et al., 2010). Aggregates of -synuclein are found in age-dependent disorders called synucleinopathies, including Parkinson&#8217;s disease (PD), Alzheimer&#8217;s disease, multiple system atrophy, and dementia with Lewy bodies (Spillantini and Goedert, 2000; Masliah et al., 2001). Both point mutations in -synuclein (A30P, E46K, A53T) (Polymeropoulos et al., 1997; Krger et al., 1998; Zarranz et al., 2004) and duplication or triplication of the -synuclein gene (Singleton et al., 2003; Ib?ez et al., 2004) produce PD. PD-linked -synuclein mutations affect -synuclein fibril formation (Conway et al., 1998, 2000; Narhi et al., 1999; Greenbaum et al., 2005; Fredenburg et al., 2007; Yonetani et al., 2009), and -synuclein oligomers are toxic to neurons (Kayed et al., 2003; Lindersson et <a href=\"https:\/\/www.adooq.com\/paris-saponin-vii.html\">Paris saponin VII<\/a> al., 2004; Tsika et al., 2010; Colla et al., 2012), suggesting that a toxic gain-of-function effect of -synuclein may produce the neurodegeneration in PD and other synucleinopathies. At least in some instances, however, the physiological function of -synuclein in promoting SNARE-complex assembly protects against neurodegeneration instead of promoting it (Chandra et al., 2005). Specifically, modest overexpression of -synuclein rescues the lethal neurodegeneration caused by deletion of CSP (cysteine string protein ), a chaperone for the SNARE-protein SNAP-25 (Sharma et al., 2011b). -Synuclein blocks neurodegeneration in CSP KO mice by compensating for <a href=\"http:\/\/www.careerclusters.org\/resources\/crosswalks\/clusters\/it.pdf\"> ZNF538<\/a> the decreased SNARE-complex assembly induced by the loss of SNAP-25 in these mice (Sharma et al., 2011a). Thus, the question arises whether -synuclein performs independent physiological functions and pathological actions, or whether pathology induced by -synuclein mutations or overexpression is related to Paris saponin VII a loss of its overall physiological function. While the pathology caused by PD-linked -synuclein mutants has been extensively Paris saponin VII compared with wild-type (WT) -synuclein, few studies have performed systematic targeted mutagenesis experiments of -synuclein to compare the consequences of various mutations for the neuropathogenic effects and physiological functions of -synuclein. Here, we set out to fill this gap in our understanding, and to clarify whether pathology in synucleinopathies is caused by a loss or gain of function of -synuclein. Toward this goal, we generated mutants of all sequence regions of human -synuclein, and examined their properties using a variety of functional and pathological readouts. Our data suggest that the physiological function and neuropathogenic effects of -synuclein are mediated by Paris saponin VII Paris saponin VII molecularly distinct processes. Materials and Methods -Synuclein expression vectors A c-myc epitope with a 4 aa linker was introduced into all expression vectors, resulting in the following N-terminal sequence: EQKLISEEDLGSGS. Introduction of stop codons or point mutations were accomplished by site-directed mutagenesis. All myc-tagged -synuclein mutants were inserted into either pGEX-KG for bacterial expression [with an N-terminal tobacco etch virus (TEV) cleavage site right before the myc epitope tag, leaving an extra N-terminal glycine upon proteolytic removal of the GST moiety], pCMV5 for expression in HEK293T cells, FUW for lentiviral expression in neuronal culture, or L302 (containing an IRES-driven GFP reporter) for lentiviral expression in substantia nigra upon stereotactic injection. Mice Synuclein triple KO mice, synaptobrevin-2 KO mice, and WT mice maintained on C57BL\/6 background were maintained and bred as described previously (Schoch et al.,.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>\ufeffPathologically, -synuclein mutations and -synuclein overexpression cause Parkinson&#8217;s disease, and aggregates of -synuclein are found as Lewy bodies in multiple neurodegenerative disorders (synucleinopathies). for its [&#8230;]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[51],"tags":[],"class_list":["post-682","post","type-post","status-publish","format-standard","hentry","category-hydrogen-atpase"],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v28.5 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>\ufeffPathologically, -synuclein mutations and -synuclein overexpression cause Parkinson&#039;s disease, and aggregates of -synuclein are found as Lewy bodies in multiple neurodegenerative disorders (synucleinopathies) - 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