One of the first molecular events in neurodegenerative diseases, regardless of etiology, is protein mislocalization. Protein mislocalization in neurons is often linked to proteostasis deficiencies leading to the build-up of misfolded proteins and/or organelles that contributes to cellular toxicity and cell death. By understanding how proteins mislocalize in neurons, we can develop novel therapeutics that target the earliest stages of neurodegeneration. A critical mechanism regulating protein localization and proteostasis in neurons is the protein-lipid modification S-acylation, the reversible addition of fatty acids to cysteine residues. S-acylation is more commonly referred to as S-palmitoylation or simply palmitoylation, which is the addition of the 16-carbon fatty acid palmitate to proteins. Like phosphorylation, palmitoylation is highly dynamic and tightly regulated by writers (i.e., palmitoyl acyltransferases) and erasers (i.e., depalmitoylating enzymes). The hydrophobic fatty acid anchors proteins to membranes; thus, the reversibility allows proteins to be re-directed to and from membranes based on local signaling factors. This is particularly important in the nervous system, where axons (output projections) can be meters long. Any disturbance in protein trafficking can have dire consequences. Indeed, many proteins involved in neurodegenerative diseases are palmitoylated, and many more have been identified in palmitoyl-proteomic studies. It follows that palmitoyl acyl transferase enzymes have also been implicated in numerous diseases. In addition, palmitoylation can work in concert with cellular mechanisms, like autophagy, to affect cell health and protein modifications, such as acetylation, nitrosylation, and ubiquitination, to affect protein function and turnover. Limited studies have further revealed a sexually dimorphic pattern of protein palmitoylation. Therefore, palmitoylation can have wide-reaching consequences in neurodegenerative diseases.
Multi-system proteinopathy (MSP) is a rare dominantly-inherited disorder that includes a cluster of diseases, including frontotemporal dementia, inclusion body myopathy, and Paget's disease of bone. MSP is caused by mutations in the gene encoding Valosin-containing protein (VCP). Patients with the same mutation, even within the same family, can present with a different combination of any or all of these diseases, along with amyotrophic lateral sclerosis (ALS). The pleiotropic effects may be linked to the greater than 50 VCP co-factors that direct VCP's many roles in the cell. Small VCP-Interacting Protein (SVIP) is a small protein that directs VCP to autophagosomes and lysosomes. We found that SVIP directs VCP localization to autophagosomes in an acylation-dependent manner. We demonstrate that SVIP is myristoylated at glycine 2 and palmitoylated at cysteines 4 and 7. Acylation of SVIP was required to mediate cell death in the presence of the MSP- associated VCP variant (R155H-VCP), whereby blocking SVIP myristoylation rescues cytotoxicity. Therefore, SVIP acylation may present a novel target in MSP.
Based on RBV and KBV, Knowledge-based training and development is potential practice for enhancing skills of employees in organizations. In this regard, current study is conducted with an aim to analyze linkage such as practiceresource-uses-performance, in which knowledge-based training and development (practice) impacts on human capital (resource), individual absorptive capacity (uses) and employee innovative behavior (performance).Data was collected through 149 faculty members of Islamabad and Rawalpindi universities (public and private). The statistical tools used for data analysis were SPSS Version -24 and Smart PLS 3.2.7. The sequential mediation was also analyzed to comprehend this linkage. Results show that Knowledge-based training and development enhances human capital which improves individual absorptive capacity and ultimately impact on employee innovative behavior positively. Based on significance of study, it is recommended to examine other knowledge-based HR practices for highlighting their importance in relation to employee's innovative behavior through Practice-resource-usesperformance linkage. Further, this model should also be applied in other service industries like tourism and telecom for generalizability of results.
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