Roles of ESCRT in autophagy-associated neurodegeneration

Gladstone Institute of Neurological Disease and Department of Neurology, Neuroscience Graduate Program, University of California, San Francisco, San Francisco, California 94158, USA.
Autophagy (Impact Factor: 11.75). 02/2008; 4(2):230-2. DOI: 10.4161/auto.5384
Source: PubMed


Autophagy is a regulated pathway for bulk degradation of cytoplasmic contents and organelles, an important process involved in many physiological and pathological conditions in multiple organs, including the nervous system. It has been proposed that developing autophagosomes fuse with late endosomal compartments before their fusion with lysosomes; however, little is known about the functional relationship between the autophagy and endocytic pathways. In the endosomal-lysosomal pathway, a key step in sorting transmembrane cargo proteins is regulated by multimeric complexes called ESCRT (endosomal sorting complex required for transport). We recently reported that dysfunction of ESCRT-III, either by depletion of its essential subunit mSnf7-2 or by expression of a mutant CHMP2B protein associated with frontotemporal dementia linked to chromosome 3 (FTD3), caused autophagosome accumulation and dendritic retraction before neurodegeneration in cultured mature cortical neurons. This defect is likely a result of an abnormal fusion process between autophagosomes and endosomal compartments or lysosomes. This study suggests that defects in the late steps of the autophagy pathway may contribute to the pathogenesis of FTD and potentially other neurodegenerative diseases.

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    • "Kim et al. 2011), and Arabidopsis thaliana (At2g19830 and At4g29160; Winter and Hauser 2006). Snf7 belongs to the ESCRT (Endosomal Sorting Complex Required for Transport)–III complex , which has been shown to be essential for sorting of transmembrane proteins en route to lysosomal degradation through the endosomal-autophagic pathway in multiple organisms (Teis et al. 2008; Rusten et al. 2008; Lee and Gao 2008; Vaccari et al. 2009; Kim et al. 2011). An assessment of spectrum of insecticidal activity for a pesticide is typically conducted during product development and is designed to characterize activity against a range of insect taxa that includes the target organism (Raybould 2006; Rose 2007; Romeis et al. 2013). "
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    ABSTRACT: The sequence specificity of the endogenous RNA interference pathway allows targeted suppression of genes essential for insect survival and enables the development of durable and efficacious insecticidal products having a low likelihood to adversely impact non-target organisms. The spectrum of insecticidal activity of a 240 nucleotide (nt) dsRNA targeting the Snf7 ortholog in Western Corn Rootworm (WCR; Diabrotica virgifera virgifera) was characterized by selecting and testing insects based upon their phylogenetic relatedness to WCR. Insect species, representing 10 families and 4 Orders, were evaluated in subchronic or chronic diet bioassays that measured potential lethal and sublethal effects. When a specific species could not be tested in diet bioassays, the ortholog to the WCR Snf7 gene (DvSnf7) was cloned and corresponding dsRNAs were tested against WCR and Colorado potato beetle (Leptinotarsa decemlineata); model systems known to be sensitive to ingested dsRNA. Bioassay results demonstrate that the spectrum of activity for DvSnf7 is narrow and activity is only evident in a subset of beetles within the Galerucinae subfamily of Chrysomelidae (>90 % identity with WCR Snf7 240 nt). This approach allowed for evaluating the relationship between minimum shared nt sequence length and activity. A shared sequence length of ≥21 nt was required for efficacy against WCR (containing 221 potential 21-nt matches) and all active orthologs contained at least three 21 nt matches. These results also suggest that WCR resistance to DvSnf7 dsRNA due to single nucleotide polymorphisms in the target sequence of 240 nt is highly unlikely. Electronic supplementary material The online version of this article (doi:10.1007/s11248-013-9716-5) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jun 2013 · Transgenic Research
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    • "[11]), and Arabidopsis thaliana (At2g19830 & At4g29160; [12]). Snf7 belongs to the ESCRT (Endosomal Sorting Complex Required for Transport)–III complex, which has been shown to be involved in sorting of transmembrane proteins en route to lysosomal degradation through the endosomal-autophagic pathway in multiple organisms [11], [13], [14], [15], [16]. The first step in the endosomal-autophagic pathway is endocytosis of membrane receptor proteins which are then delivered to early endosomes from where they are either recycled to the plasma membrane or sorted to the lysosome for degradation [17], [18], [19]. "
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    ABSTRACT: Ingestion of double stranded RNA (dsRNA) has been previously demonstrated to be effective in triggering RNA interference (RNAi) in western corn rootworm (WCR, Diabrotica virgifera virgifera LeConte), providing potential novel opportunities for insect pest control. The putative Snf7 homolog of WCR (DvSnf7) has previously been shown to be an effective RNAi target for insect control, as DvSnf7 RNAi leads to lethality of WCR larvae. Snf7 functions as a part of the ESCRT (Endosomal Sorting Complex Required for Transport) pathway which plays a crucial role in cellular housekeeping by internalization, transport, sorting and lysosomal degradation of transmembrane proteins. To understand the effects that lead to death of WCR larvae by DvSnf7 RNAi, we examined some of the distinct cellular processes associated with ESCRT functions such as de-ubiquitination of proteins and autophagy. Our data indicate that ubiquitinated proteins accumulate in DvSnf7 dsRNA-fed larval tissues and that the autophagy process seems to be impaired. These findings suggest that the malfunctioning of these cellular processes in both midgut and fat body tissues triggered by DvSnf7 RNAi were the main effects leading to the death of WCR. This study also illustrates that Snf7 is an essential gene in WCR and its functions are consistent with biological functions described for other eukaryotes.
    Full-text · Article · Jan 2013 · PLoS ONE
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    • "during the course of these pathologies [30]. It has been ascertained that mutations or any kind of alteration targeting the endosomal-lysosomal machinery, with MVB acting at the intersection point, gives rise to defective endosomal sorting and possible neuronal demise [31] [32] [33] [34] [35]. Alternatively, some authors have put forward the hypothesis of a neuroprotective role for MVB/late endosomes and lysosomes by means of taking over the aberrant proteins [36]. "
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    ABSTRACT: A growing body of research deals with the relationship between the endosomal and autophagic/lysosomal pathways during developmental stages of the central nervous system. This includes their possible influence regarding the onset and progression of specific neurodegenerative disorders. In this review we focus our attention on major alterations affecting two organelles: autophagosomes and multivesicular bodies, both of which are located at the intersection point of their respective pathways.
    Full-text · Article · Dec 2012
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