scholarly journals Ref(2)P, the Drosophila melanogaster homologue of mammalian p62, is required for the formation of protein aggregates in adult brain

2008 ◽  
Vol 180 (6) ◽  
pp. 1065-1071 ◽  
Author(s):  
Ioannis P. Nezis ◽  
Anne Simonsen ◽  
Antonia P. Sagona ◽  
Kim Finley ◽  
Sébastien Gaumer ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Protein Aggregates ◽  
Adult Brain ◽  
Aggregate Formation ◽  
Ubiquitinated Protein ◽  
Physiological Conditions ◽  
Binding Domains ◽  
Ubiquitin Binding ◽  
Autophagic Degradation

p62 has been proposed to mark ubiquitinated protein bodies for autophagic degradation. We report that the Drosophila melanogaster p62 orthologue, Ref(2)P, is a regulator of protein aggregation in the adult brain. We demonstrate that Ref(2)P localizes to age-induced protein aggregates as well as to aggregates caused by reduced autophagic or proteasomal activity. A similar localization to protein aggregates is also observed in D. melanogaster models of human neurodegenerative diseases. Although atg8a autophagy mutant flies show accumulation of ubiquitin- and Ref(2)P-positive protein aggregates, this is abrogated in atg8a/ref(2)P double mutants. Both the multimerization and ubiquitin binding domains of Ref(2)P are required for aggregate formation in vivo. Our findings reveal a major role for Ref(2)P in the formation of ubiquitin-positive protein aggregates both under physiological conditions and when normal protein turnover is inhibited.

scholarly journals The scaffold protein EPG-7 links cargo–receptor complexes with the autophagic assembly machinery

2013 ◽  
Vol 201 (1) ◽  
pp. 113-129 ◽  
Author(s):  
Long Lin ◽  
Peiguo Yang ◽  
Xinxin Huang ◽  
Hui Zhang ◽  
Qun Lu ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Protein Aggregates ◽  
Scaffold Protein ◽  
Receptor Complex ◽  
Interacting Proteins ◽  
Physiological Conditions ◽  
Receptor Complexes ◽  
Atg Proteins ◽  
Cargo Receptor ◽  
Autophagic Degradation

The mechanism by which protein aggregates are selectively degraded by autophagy is poorly understood. Previous studies show that a family of Atg8-interacting proteins function as receptors linking specific cargoes to the autophagic machinery. Here we demonstrate that during Caenorhabditis elegans embryogenesis, epg-7 functions as a scaffold protein mediating autophagic degradation of several protein aggregates, including aggregates of the p62 homologue SQST-1, but has little effect on other autophagy-regulated processes. EPG-7 self-oligomerizes and is degraded by autophagy independently of SQST-1. SQST-1 directly interacts with EPG-7 and colocalizes with EPG-7 aggregates in autophagy mutants. Mutations in epg-7 impair association of SQST-1 aggregates with LGG-1/Atg8 puncta. EPG-7 interacts with multiple ATG proteins and colocalizes with ATG-9 puncta in various autophagy mutants. Unlike core autophagy genes, epg-7 is dispensable for starvation-induced autophagic degradation of substrate aggregates. Our results indicate that under physiological conditions a scaffold protein endows cargo specificity and also elevates degradation efficiency by linking the cargo–receptor complex with the autophagic machinery.

scholarly journals Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease

2007 ◽  
Vol 179 (3) ◽  
pp. 485-500 ◽  
Author(s):  
Maria Filimonenko ◽  
Susanne Stuffers ◽  
Camilla Raiborg ◽  
Ai Yamamoto ◽  
Lene Malerød ◽  
...  
Keyword(s):  
Multivesicular Body ◽  
Protein Aggregates ◽  
Multivesicular Bodies ◽  
Ubiquitinated Protein ◽  
Endosomal Sorting ◽  
Ubiquitinated Proteins ◽  
Protein Deposits ◽  
Autophagic Degradation ◽  
Lateral Sclerosis ◽  
In Cells

The endosomal sorting complexes required for transport (ESCRTs) are required to sort integral membrane proteins into intralumenal vesicles of the multivesicular body (MVB). Mutations in the ESCRT-III subunit CHMP2B were recently associated with frontotemporal dementia and amyotrophic lateral sclerosis (ALS), neurodegenerative diseases characterized by abnormal ubiquitin-positive protein deposits in affected neurons. We show here that autophagic degradation is inhibited in cells depleted of ESCRT subunits and in cells expressing CHMP2B mutants, leading to accumulation of protein aggregates containing ubiquitinated proteins, p62 and Alfy. Moreover, we find that functional MVBs are required for clearance of TDP-43 (identified as the major ubiquitinated protein in ALS and frontotemporal lobar degeneration with ubiquitin deposits), and of expanded polyglutamine aggregates associated with Huntington's disease. Together, our data indicate that efficient autophagic degradation requires functional MVBs and provide a possible explanation to the observed neurodegenerative phenotype seen in patients with CHMP2B mutations.

scholarly journals p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death

2005 ◽  
Vol 171 (4) ◽  
pp. 603-614 ◽  
Author(s):  
Geir Bjørkøy ◽  
Trond Lamark ◽  
Andreas Brech ◽  
Heidi Outzen ◽  
Maria Perander ◽  
...  
Keyword(s):  
Cell Death ◽  
Protective Effect ◽  
Cell Survival ◽  
Light Chain ◽  
Protein Aggregates ◽  
Mutant Huntingtin ◽  
Ubiquitinated Protein ◽  
Protein Levels ◽  
Autophagic Degradation ◽  
Starvation Conditions

Autophagic degradation of ubiquitinated protein aggregates is important for cell survival, but it is not known how the autophagic machinery recognizes such aggregates. In this study, we report that polymerization of the polyubiquitin-binding protein p62/SQSTM1 yields protein bodies that either reside free in the cytosol and nucleus or occur within autophagosomes and lysosomal structures. Inhibition of autophagy led to an increase in the size and number of p62 bodies and p62 protein levels. The autophagic marker light chain 3 (LC3) colocalized with p62 bodies and coimmunoprecipitated with p62, suggesting that these two proteins participate in the same complexes. The depletion of p62 inhibited recruitment of LC3 to autophagosomes under starvation conditions. Strikingly, p62 and LC3 formed a shell surrounding aggregates of mutant huntingtin. Reduction of p62 protein levels or interference with p62 function significantly increased cell death that was induced by the expression of mutant huntingtin. We suggest that p62 may, via LC3, be involved in linking polyubiquitinated protein aggregates to the autophagy machinery.

scholarly journals Hormonal Regulation of Oligodendrogenesis I: Effects across the Lifespan

2021 ◽  
Author(s):  
Kimberly Long ◽  
Jocelyn Breton ◽  
Matthew Barraza ◽  
Olga Litvin ◽  
Daniela Kaufer
Keyword(s):  
Immune System ◽  
Hormonal Regulation ◽  
Mechanisms Of Action ◽  
Adult Brain ◽  
Physiological Conditions ◽  
Changing Environments ◽  
Complex Interactions ◽  
Specific Receptors ◽  
The Brain

The brain’s capacity to respond to changing environments via hormonal signaling is critical to fine-tuned function. An emerging body of literature highlights a role for myelin plasticity as a prominent type of experience-dependent plasticity in the adult brain. Myelin plasticity is driven by oligodendrocytes (OLs) and their precursor cells (OPCs). OPC differentiation regulates the trajectory of myelin production throughout development, and importantly, OPCs maintain the ability to proliferate and generate new OLs throughout adulthood. The process of oligodendrogenesis (OLgenesis), the creation of new OLs, can be dramatically influenced during early development and in adulthood by internal and environmental conditions such as hormones. Here, we review the current literature describing hormonal regulation of OLgenesis within physiological conditions, focusing on several classes of hormones: steroid, peptide, and thyroid hormones. We discuss hormonal regulation at each stage of OLgenesis and describe mechanisms of action, where known. Overall, the majority of hormones enhance OLgenesis, increasing OPC differentiation and inducing maturation and myelin production in OLs. The mechanisms underlying these processes vary for each hormone but may ultimately converge upon common signaling pathways, mediated by specific receptors expressed across the OL lineage. However, not all of the mechanisms have been fully elucidated, and here, we note the remaining gaps in the literature, including the complex interactions between hormonal systems and with the immune system. In the companion manuscript in this issue [1], we discuss the implications of hormonal regulation of OLgenesis for neurological and psychiatric disorders characterized by white matter loss. Ultimately, a better understanding of the fundamental mechanisms of hormonal regulation of OLgenesis across the entire lifespan, especially in vivo, will progress both basic and translational research.

scholarly journals Oligomerization of Selective Autophagy Receptors for the Targeting and Degradation of Protein Aggregates

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1989
Author(s):  
Wenjun Chen ◽  
Tianyun Shen ◽  
Lijun Wang ◽  
Kefeng Lu
Keyword(s):  
Phase Separation ◽  
Binding Protein ◽  
Protein Aggregates ◽  
Selective Autophagy ◽  
Binding Domains ◽  
Selective Targeting ◽  
Ubiquitin Binding

The selective targeting and disposal of solid protein aggregates are essential for cells to maintain protein homoeostasis. Autophagy receptors including p62, NBR1, Cue5/TOLLIP (CUET), and Tax1-binding protein 1 (TAX1BP1) proteins function in selective autophagy by targeting ubiquitinated aggregates through ubiquitin-binding domains. Here, we summarize previous beliefs and recent findings on selective receptors in aggregate autophagy. Since there are many reviews on selective autophagy receptors, we focus on their oligomerization, which enables receptors to function as pathway determinants and promotes phase separation.

scholarly journals Activation of a neural stem cell transcriptional program in parenchymal astrocytes

2020 ◽  
Author(s):  
Jens P. Magnusson ◽  
Margherita Zamboni ◽  
Giuseppe Santopolo ◽  
Jeff E. Mold ◽  
Mauricio Barrientos-Somarribas ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Subventricular Zone ◽  
Brain Regions ◽  
Adult Brain ◽  
Targeted Interventions ◽  
Physiological Conditions ◽  
Neuronal Lineage ◽  
Epidermal Growth

AbstractNeural stem cells, located in discrete niches in the adult brain, generate new neurons throughout life. These stem cells are specialized astrocytes, but astrocytes in other brain regions do not generate neurons under physiological conditions. After stroke, however, striatal astrocytes undergo neurogenesis in mice, triggered by decreased Notch signaling. We used single-cell RNA sequencing to characterize neurogenesis by Notch-depleted striatal astrocytes in vivo. Striatal astrocytes were located upstream of neural stem cells in the neuronal lineage. As astrocytes initiated neurogenesis, they became transcriptionally very similar to subventricular zone stem cells and progressed through a nearly identical neurogenic program. Surprisingly, in the non- neurogenic cortex, Notch-depleted astrocytes also initiated neurogenesis. Yet, the cortical astrocytes, and many striatal ones, stalled before entering transit- amplifying divisions. Infusion of epidermal growth factor enabled stalled striatal astrocytes to resume neurogenesis. We conclude that parenchymal astrocytes are latent neural stem cells and that targeted interventions can guide them through their neuronal differentiation.

scholarly journals Hormonal Regulation of Oligodendrogenesis I: Effects across the Lifespan

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 283 ◽  
Author(s):  
Kimberly L. P. Long ◽  
Jocelyn M. Breton ◽  
Matthew K. Barraza ◽  
Olga S. Perloff ◽  
Daniela Kaufer
Keyword(s):  
Immune System ◽  
White Matter ◽  
Hormonal Regulation ◽  
Mechanisms Of Action ◽  
Adult Brain ◽  
Physiological Conditions ◽  
Changing Environments ◽  
Complex Interactions ◽  
Specific Receptors

The brain’s capacity to respond to changing environments via hormonal signaling is critical to fine-tuned function. An emerging body of literature highlights a role for myelin plasticity as a prominent type of experience-dependent plasticity in the adult brain. Myelin plasticity is driven by oligodendrocytes (OLs) and their precursor cells (OPCs). OPC differentiation regulates the trajectory of myelin production throughout development, and importantly, OPCs maintain the ability to proliferate and generate new OLs throughout adulthood. The process of oligodendrogenesis, the creation of new OLs, can be dramatically influenced during early development and in adulthood by internal and environmental conditions such as hormones. Here, we review the current literature describing hormonal regulation of oligodendrogenesis within physiological conditions, focusing on several classes of hormones: steroid, peptide, and thyroid hormones. We discuss hormonal regulation at each stage of oligodendrogenesis and describe mechanisms of action, where known. Overall, the majority of hormones enhance oligodendrogenesis, increasing OPC differentiation and inducing maturation and myelin production in OLs. The mechanisms underlying these processes vary for each hormone but may ultimately converge upon common signaling pathways, mediated by specific receptors expressed across the OL lineage. However, not all of the mechanisms have been fully elucidated, and here, we note the remaining gaps in the literature, including the complex interactions between hormonal systems and with the immune system. In the companion manuscript in this issue, we discuss the implications of hormonal regulation of oligodendrogenesis for neurological and psychiatric disorders characterized by white matter loss. Ultimately, a better understanding of the fundamental mechanisms of hormonal regulation of oligodendrogenesis across the entire lifespan, especially in vivo, will progress both basic and translational research.

Insights into amyloid disease from fly models

2014 ◽  
Vol 56 ◽  
pp. 69-83 ◽  
Author(s):  
Ko-Fan Chen ◽  
Damian C. Crowther
Keyword(s):  
Drosophila Melanogaster ◽  
Neurodegenerative Disorders ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Disease Pathogenesis ◽  
Amyloid Aggregates ◽  
Aβ Amyloid ◽  
Polypeptide Chains ◽  
Amyloid Diseases

The formation of amyloid aggregates is a feature of most, if not all, polypeptide chains. In vivo modelling of this process has been undertaken in the fruitfly Drosophila melanogaster with remarkable success. Models of both neurological and systemic amyloid diseases have been generated and have informed our understanding of disease pathogenesis in two main ways. First, the toxic amyloid species have been at least partially characterized, for example in the case of the Aβ (amyloid β-peptide) associated with Alzheimer's disease. Secondly, the genetic underpinning of model disease-linked phenotypes has been characterized for a number of neurodegenerative disorders. The current challenge is to integrate our understanding of disease-linked processes in the fly with our growing knowledge of human disease, for the benefit of patients.

Supramolecular Enhancement of Aminoxyl ORCA Contrast Agents

2019 ◽  
Author(s):  
Hamilton Lee ◽  
Jenica Lumata ◽  
Michael A. Luzuriaga ◽  
Candace Benjamin ◽  
Olivia Brohlin ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Side Effects ◽  
Magnetic Resonance ◽  
Tobacco Mosaic Virus ◽  
Contrast Agents ◽  
Single Molecule ◽  
Organic Radical ◽  
Resonance Imaging ◽  
Physiological Conditions

<div><div><div><p>Many contrast agents for magnetic resonance imaging are based on gadolinium, however side effects limit their use in some patients. Organic radical contrast agents (ORCAs) are potential alternatives, but are reduced rapidly in physiological conditions and have low relaxivities as single molecule contrast agents. Herein, we use a supramolecular strategy where cucurbit[8]uril binds with nanomolar affinities to ORCAs and protects them against biological reductants to create a stable radical in vivo. We further over came the weak contrast by conjugating this complex on the surface of a self-assembled biomacromolecule derived from the tobacco mosaic virus.</p></div></div></div>

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