One of the possible interactors identified was Ras-like in rat mind 7A (Rab7A), a protein involved in autophagy and phagocytosis in and additional organisms (Guerra and Bucci, 2016; Rupper et al., 2001). between mitochondria-endosomes and mitochondria-endoplasmic reticulum and that the presence of membrane XMD16-5 contact sites is modified in the absence of VPS13A. Based on these findings, we propose that restorative strategies aimed at modulating the endolysosomal pathway could be beneficial in the treatment of ChAc. This short article has an connected First Person interview with the first author of the paper. lead to Cohen syndrome XMD16-5 (Kolehmainen et al., 2003); mutations in have been identified as a cause of an autosomal-recessive, early-onset and severe form of Parkinson’s disease (Lesage et al., 2016; Schormair et al., 2018); and, most recently, mutations in have been linked to additional movement disorders (Gauthier et al., 2018; Seong et al., 2018). In addition, genomic data have identified variants in additional neurological disorders (Fromer et al., 2014; McCarthy et al., 2014; Meda et al., 2012), in various types of malignancy (An et al., 2012; Furukawa et al., 2011; Morisaki et al., 2014; Park et al., 2016b; Yang et al., 2016b) and in diabetes (Grarup et al., 2011; Saxena et al., 2010; Strawbridge et al., 2011; Windholz et al., 2011). VPS13 proteins are very large proteins that share conserved domains or structural features. They may be widely conserved during eukaryotic development, from unicellular organisms to humans (Velayos-Baeza et al., 2004), so their study can be addressed in different models (Rzepnikowska et al., 2017). In and as a model organism and then human being cells. Our results suggest that the problems observed in autophagy in the absence of VPS13A are most likely the consequence of a more general impairment of the endolysosomal pathway. In addition, we investigated the subcellular localization of VPS13A and found an unexpected predominant localization to mitochondria, which provides useful insight into the possible mechanisms by which the absence of VPS13A may lead to lysosomal dysfunction. RESULTS RAB7A interacts with TipC and human XMD16-5 being VPS13A Our earlier study of a member of the VPS13 family, TipC, in offered the first evidence of VPS13 proteins involvement in autophagy. The mutant presents a multitipped phenotype, which is a characteristic developmental phenotype of autophagy mutants with this interpersonal amoeba (Mesquita et al., 2015; Otto et al., 2003, 2004; Tung et al., 2010), and, accordingly, this mutant exhibits impaired autophagy along with additional problems in sporulation and phagocytosis. We found that these phenotypes were largely rescued from the overexpression of the C-terminal region of TipC (amino acids 2725-3848), which contains conserved domains found in virtually all VPS13 proteins, including human being VPS13A. In addition, we shown that autophagy is definitely impaired in VPS13A-depleted human MGC102953 being HeLa cells (Mu?oz-Braceras et al., 2015). Based on these results, we hypothesized the C-terminal region of TipC in could mediate its connection with proteins involved in the execution or rules of autophagy and that this interaction could be conserved for human being VPS13A. Therefore, in the present study, we used as a starting point to shed light on the molecular function of VPS13 proteins. We used liquid chromatography (LC) coupled to tandem mass spectrometry (MS/MS) to identify proteins that co-immunoprecipitate with TipC2725-3848-GFP and not having a control GFP (Table?S1). One of the possible interactors recognized was Ras-like in rat mind 7A (Rab7A), a protein involved in autophagy and phagocytosis in and additional organisms (Guerra and Bucci, 2016; Rupper et al., 2001). The connection was confirmed by pulldown experiments using cells expressing hemagglutinin (HA)-tagged Rab7A and TipC2725-3848-GFP (Fig.?1A). We then analyzed the connection of the related human being proteins in HeLa cells transfected with GFP-tagged wild-type or mutant constitutively active (GTP-bound) or constitutively inactive (GDP-bound) forms of the RAB7A GTPase. We observed that endogenous VPS13A specifically co-immunoprecipitated with GFP-RAB7A, and that VPS13A interacts more with.