Mitochondrial Quality Control: Decommissioning Power Plants in Neurodegenerative Diseases

The cell has an intricate quality control system to protect its mitochondria from oxidative stress. This surveillance system is multi-tiered and comprises molecules that are present inside the mitochondria, in the cytosol, and in other organelles like the nucleus and endoplasmic reticulum. These molecules cross talk with each other and protect the mitochondria from oxidative stress. Oxidative stress is a fundamental part of early disease pathogenesis of neurodegenerative diseases. These disorders also damage the cellular quality control machinery that protects the cell against oxidative stress. This exacerbates the oxidative damage and causes extensive neuronal cell death that is characteristic of neurodegeneration

Reduced Translocation of Nascent Prion Protein During ER Stress Contributes to Neurodegeneration

SummaryDuring acute stress in the endoplasmic reticulum (ER), mammalian prion protein (PrP) is temporarily prevented from translocation into the ER and instead routed directly for cytosolic degradation. This “pre-emptive” quality control (pQC) system benefits cells by minimizing PrP aggregation in the secretory pathway during ER stress. However, the potential toxicity of cytosolic PrP raised the possibility that persistent pQC of PrP contributes to neurodegeneration in prion diseases. Here, we find evidence of ER stress and decreased translocation of nascent PrP during prion infection. Transgenic mice expressing a PrP variant with reduced translocation at levels expected during ER stress was sufficient to cause several mild age-dependent clinical and histological manifestations of PrP-mediated neurodegeneration. Thus, an ordinarily adaptive quality-control pathway can be contextually detrimental over long time periods. We propose that one mechanism of prion-mediated neurodegeneration involves an indirect ER stress-dependent effect on nascent PrP biosynthesis and metabolism

Signal sequence insufficiency contributes to neurodegeneration caused by transmembrane prion protein

Improving the efficiency of PrP translocation into the ER decreases levels of transmembrane bound protein and rescues mice from prion disease

Compartment-Restricted Biotinylation Reveals Novel Features of Prion Protein Metabolism in Vivo

A selective tagging method for detecting minor alternatively-localized populations of a protein is used to study a disease-associated transmembrane form of prion protein. The analysis reveals key features of transmembrane prion protein metabolism and one way this is altered by human disease-causing mutants

ESCRTs AND ASSOCIATED PROTEINS IN LYSOSOMAL FUSION WITH ENDOSOMES AND AUTOPHAGOSOMES

Endo-lysosomal and autophagosomal degradation pathways are highly connected at various levels, sharing multiple molecular effectors that modulate them individually or simultaneously. These two lysosomal degradative pathways are primarily involved in the disposal of cargo internalized from the cell surface or long lived proteins or aggregates and aged organelles present in the cytosol. Both these pathways involve a number of carefully regulated vesicular fusion events which are dependent on ESCRT proteins. The ESCRT proteins especially ESCRT-I and III participate in the regulation of fusion events between autophagosome/amphisome and lysosome. Along with these, a number of functionally diverse ESCRT associated and regulatory proteins such as, endosomal PtdIns (3) P 5-kinase Fab1, ALIX, Mahogunin RING Finger1, Atrogin1, Syntaxin17, ATG12-ATG3 complex and Protein kinase CK2Îą are involved in fusion events in either or both the lysosomal degradative pathways.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission

Abstract Dynamin related protein 1 (DRP1), a pivotal mitochondrial fission protein, is post-translationally modified by multiple mechanisms. Here we identify a new post-translational modification of DRP1 by the ubiquitin-like protein, interferon-stimulated gene 15 (ISG15). DRP1 ISGylation is mediated by ISG15 E3 ligase, HERC5; this promotes mitochondrial fission. DeISGylation of DRP1 however leads to hyperfusion. Heterologous expression of SARS-CoV2 PLpro, a deISGylating enzyme, results in similar mitochondrial filamentation, significant decrease in total DRP1 protein levels and efflux of mtDNA. We report that deISGylated DRP1 gets ubiquitylated and degraded by TRIM25, instead of PARKIN and MITOL. While the cytosolic pool of DRP1 is primarily ISGylated, both mitochondrial and cytosolic fractions may be ubiquitylated. It is known that phosphorylation of DRP1 at S616 residue regulates its mitochondrial localisation; we show that ISGylation of phospho-DRP1 (S616) renders fission competence at mitochondria. This is significant because DRP1 ISGylation affects its functionality and mitochondrial dynamics in Alzheimer’s disease pathophysiology

Ubiquitin in Regulation of Spindle Apparatus and its Positioning: Implications in Development and Disease

Emerging data implicates ubiquitination, a post-translational modification, in regulating essential cellular events -- one of them being mitosis. In this review we discuss how various E3 ligases modulate the cortical proteins, like, dynein, LGN, NuMa, GαThe accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

MAHOGUNIN MEDIATED REGULATION OF Gαi LOCALISATION DURING MITOSIS AND ITS EFFECT ON SPINDLE POSITIONING

Mahogunin RING Finger 1 (MGRN1) is a ubiquitin E3 ligase known to affect spindle tilt in mitotic cells by regulating α-tubulin ubiquitination and polymerization. In cell culture systems we have found that expressing truncated mutants of MGRN1 lead to various other mitotic anomalies, like lateral and angular spindle displacements. This seems independent of the MGRN1 ligase activity. Our experiments suggest that MGRN1 regulates the balance between the lower molecular weight monomeric Gαi and larger trimeric G-protein complex, along with its abundance in the ternary complex that regulates spindle positioning. The cytosolic isoforms of MGRN1 lead to the enrichment of monomeric Gαi in the cytosol and its subsequent recruitment at the plasma membrane. Excess of Gαi at the cell cortex results in an imbalance in the assembly of the ternary complex regulating spindle positioning during mitosis. These observations seem independent of the ligase activity of MGRN1 though we cannot negate the involvement of an intermediate player which acts as a substrate for MGRN1 and in turn, regulates Gαi.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author