scholarly journals The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote aggrephagy

2017 ◽  
Vol 216 (5) ◽  
pp. 1301-1320 ◽  
Author(s):  
Xuezhao Liu ◽  
Yang Li ◽  
Xin Wang ◽  
Ruxiao Xing ◽  
Kai Liu ◽  
...  
Keyword(s):  
Quality Control ◽  
Essential Role ◽  
Developmental Disorder ◽  
Protein Quality ◽  
Striatal Neurons ◽  
Wd40 Repeat ◽  
Ubiquitinated Proteins ◽  
Underlying Mechanisms ◽  
The Brain

Autophagy-dependent clearance of ubiquitinated and aggregated proteins is critical to protein quality control, but the underlying mechanisms are not well understood. Here, we report the essential role of the BEACH (beige and Chediak–Higashi) and WD40 repeat-containing protein WDR81 in eliminating ubiquitinated proteins through autophagy. WDR81 associates with ubiquitin (Ub)-positive protein foci, and its loss causes accumulation of Ub proteins and the autophagy cargo receptor p62. WDR81 interacts with p62, facilitating recognition of Ub proteins by p62. Furthermore, WDR81 interacts with LC3C through canonical LC3-interacting regions in the BEACH domain, promoting LC3C recruitment to ubiquitinated proteins. Inactivation of LC3C or defective autophagy results in accumulation of Ub protein aggregates enriched for WDR81. In mice, WDR81 inactivation causes accumulation of p62 bodies in cortical and striatal neurons in the brain. These data suggest that WDR81 coordinates p62 and LC3C to facilitate autophagic removal of Ub proteins, and provide important insights into CAMRQ2 syndrome, a WDR81-related developmental disorder.

scholarly journals TTC3-Mediated Protein Quality Control, A Potential Mechanism for Cognitive Impairment

2021 ◽  
Author(s):  
Xu Zhou ◽  
Xiongjin Chen ◽  
Tingting Hong ◽  
Miaoping Zhang ◽  
Yujie Cai ◽  
...  
Keyword(s):  
Quality Control ◽  
Cognitive Impairment ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Research Progress ◽  
Repeat Domain ◽  
Ubiquitin Proteasome ◽  
Domain 3

AbstractThe tetrapeptide repeat domain 3 (TTC3) gene falls within Down's syndrome (DS) critical region. Cognitive impairment is a common phenotype of DS and Alzheimer’s disease (AD), and overexpression of TTC3 can accelerate cognitive decline, but the specific mechanism is unknown. The TTC3-mediated protein quality control (PQC) mechanism, similar to the PQC system, is divided into three parts: it acts as a cochaperone to assist proteins in folding correctly; it acts as an E3 ubiquitin ligase (E3s) involved in protein degradation processes through the ubiquitin–proteasome system (UPS); and it may also eventually cause autophagy by affecting mitochondrial function. Thus, this article reviews the research progress on the structure, function, and metabolism of TTC3, including the recent research progress on TTC3 in DS and AD; the role of TTC3 in cognitive impairment through PQC in combination with the abovementioned attributes of TTC3; and the potential targets of TTC3 in the treatment of such diseases.

scholarly journals Bidirectional asymmetry in the neurovisceral communication for the cardiovascular control: New insights

2017 ◽  
Vol 51 (3) ◽  
pp. 157-167 ◽  
Author(s):  
I Prieto ◽  
AB Segarra ◽  
M Martinez-Canamero ◽  
M De Gasparo ◽  
S Zorad ◽  
...  
Keyword(s):  
Essential Role ◽  
Renin Angiotensin System ◽  
Cardiovascular Function ◽  
Cardiovascular Control ◽  
Functional Connection ◽  
Angiotensin System ◽  
Positive Correlations ◽  
Available Information ◽  
The Brain

AbstractThe cardiovascular control involves a bidirectional functional connection between the brain and heart. We hypothesize that this connection could be extended to other organs using endocrine and autonomic nervous systems (ANS) as communication pathways. This implies a neuroendocrine interaction controlling particularly the cardiovascular function where the enzymatic cascade of the renin-angiotensin system (RAS) plays an essential role. It acts not only through its classic endocrine connection but also the ANS. In addition, the brain is functionally, anatomically, and neurochemically asymmetric. Moreover, this asymmetry goes even beyond the brain and it includes both sides of the peripheral nervous and neuroendocrine systems. We revised the available information and analyze the asymmetrical neuroendocrine bidirectional interaction for the cardiovascular control. Negative and positive correlations involving the RAS have been observed between brain, heart, kidney, gut, and plasma in physiologic and pathologic conditions. The central role of the peptides and enzymes of the RAS within this neurovisceral communication, as well as the importance of the asymmetrical distribution of the various RAS components in the pathologies involving this connection, are particularly discussed. In conclusion, there are numerous evidences supporting the existence of a neurovisceral connection with multiorgan involvement that controls, among others, the cardiovascular function. This connection is asymmetrically organized.

scholarly journals Cdc48 regulates intranuclear quality control sequestration of the Hsh155 splicing factor

2020 ◽  
Author(s):  
Veena Mathew ◽  
Arun Kumar ◽  
Yangyang Kate Jiang ◽  
Kyra West ◽  
Annie S Tam ◽  
...  
Keyword(s):  
Quality Control ◽  
Essential Role ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Genotoxic Stress ◽  
Stress Conditions ◽  
Splicing Factor ◽  
Misfolded Proteins ◽  
Dna Complexes ◽  
Partner Proteins

Cdc48/VCP is a highly conserved ATPase chaperone that plays an essential role in the assembly or disassembly of protein-DNA complexes and in degradation of misfolded proteins. We find that Cdc48 accumulates during cellular stress at intranuclear protein quality control (INQ) sites. Cdc48 function is required to suppress INQ formation under non-stress conditions and to promote recovery following genotoxic stress. Cdc48 physically associates with the INQ substrate and splicing factor Hsh155 and regulates its assembly with partner proteins. Accordingly, cdc48 mutants have defects in splicing and show spontaneous distribution of Hsh155 to INQ aggregates where it is stabilized. Overall, this study shows that Cdc48 regulates deposition of proteins at INQ and suggests a previously unknown role for Cdc48 in the regulation or stability of splicing subcomplexes.

Forward Dendritic Spikes

2011 ◽  
pp. 42-59
Author(s):  
Oscar Herreras ◽  
Julia Makarova ◽  
José Manuel Ibarz
Keyword(s):  
Action Potentials ◽  
Remarkable Property ◽  
Synaptic Inputs ◽  
Brain Circuits ◽  
Voltage Dependent ◽  
Dendritic Spikes ◽  
Underlying Mechanisms ◽  
The Brain ◽  
Made In

Neurons send trains of action potentials to communicate each other. Different messages are issued according to varying inputs, but they can also mix them up in a multiplexed language transmitted through a single cable, the axon. This remarkable property arises from the capability of dendritic domains to work semi autonomously and even decide output. We review the underlying mechanisms and theoretical implications of the role of voltage-dependent dendritic currents on the forward transmission of synaptic inputs, with special emphasis in the initiation, integration and forward conduction of dendritic spikes. When these spikes reach the axon, output decision was made in one of many parallel dendritic substations. When failed, they still serve as an internal language to transfer information between dendritic domains. This notion brakes with the classic view of neurons as the elementary units of the brain and attributes them computational/storage capabilities earlier billed to complex brain circuits.

PINK1/Parkin in Neurodegenerative Disorders

2020 ◽  
pp. 282-301 ◽  
Author(s):  
Mukesh Pandey ◽  
Shakir Saleem ◽  
Himani Nautiyal ◽  
Faheem Hyder Pottoo ◽  
Md. Noushad Javed
Keyword(s):  
Quality Control ◽  
Neurodegenerative Disorders ◽  
Protein Quality ◽  
Surveillance Systems ◽  
Mutant Proteins ◽  
Subsequent Effect ◽  
Pink1 Gene ◽  
Disease Cell ◽  
Early Onset Parkinson’S Disease

PTEN-induced kinase 1 (PINK1), a mitochondrial serine/threonine-protein kinase encoded by the PINK1 gene, is thought to protect cells from stress-induced mitochondrial dysfunction. The activity of PINK1 facilitates the binding of Parkin protein with depolarized mitochondria to induce autophagy. Mutations of PINK1causes a type of autosomal recessive early-onset Parkinson's disease. Cell depends on the surveillance systems or mechanisms like protein quality control to handle the alterations in the proteins that are induced because of these mutations. These mutant proteins are found to be pathogenic and are reported to be related to various neurodegenerative disorders. This chapter focuses on the role of PINK1/Parkin in mitochondria quality control and its subsequent effect in neurodegeneration.

Protein Quality Control in Neurodegeneration and Neuroprotection

2020 ◽  
pp. 1-24
Author(s):  
Yasmeena Akhter ◽  
Jahangir Nabi ◽  
Hinna Hamid ◽  
Nahida Tabassum ◽  
Faheem Hyder Pottoo ◽  
...  
Keyword(s):  
Quality Control ◽  
Neurodegenerative Disorders ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Security System ◽  
Conformational Disorders ◽  
Ubiquitin Proteasome ◽  
Multi Level

Proteostasis is essential for regulating the integrity of the proteome. Disruption of proteostasis under some rigorous conditions leads to the aggregation and accumulation of misfolded toxic proteins, which plays a central role in the pathogenesis of protein conformational disorders. The protein quality control (PQC) system serves as a multi-level security system to shield cells from abnormal proteins. The intrinsic PQC systems maintaining proteostasis include the ubiquitin-proteasome system (UPS), chaperon-mediated autophagy (CMA), and autophagy-lysosome pathway (ALP) that serve to target misfolded proteins for unfolding, refolding, or degradation. Alterations of PQC systems in neurons have been implicated in the pathogenesis of various neurodegenerative disorders. This chapter provides an overview of PQC pathways to set a framework for discussion of the role of PQC in neurodegenerative disorders. Additionally, various pharmacological approaches targeting PQC are summarized.

scholarly journals Prions and the lymphoreticular system

2001 ◽  
Vol 356 (1406) ◽  
pp. 177-184 ◽  
Author(s):  
Charles Weissmann ◽  
Alex J. Raeber ◽  
Fabio Montrasio ◽  
Ivan Hegyi ◽  
Rico Frigg ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
B Lymphocytes ◽  
Knockout Mice ◽  
Essential Role ◽  
Follicular Dendritic Cells ◽  
Splenic Lymphocytes ◽  
Β Receptor ◽  
The Brain

Following intracerebral or peripheral inoculation of mice with scrapie prions, infectivity accumulates first in the spleen and only later in the brain. In the spleen of scrapie–infected mice, prions were found in association with T and B lymphocytes and to a somewhat lesser degree with the stroma, which contains the follicular dendritic cells (FDCs) but not with non–B, non–T cells; strikingly, no infectivity was found in lymphocytes from blood of the same mice. Transgenic PrP knockout mice expressing PrP restricted to either B or T lymphocytes show no prion replication in the lymphoreticular system. Therefore, splenic lymphocytes either acquire prions from another source or replicate them in dependency on other PrP–expressing cells. The essential role of FDCs in prion replication in spleen was shown by treating mice with soluble lymphotoxin–β receptor, which led to disappearance of mature FDCs from the spleen and concomitantly abolished splenic prion accumulation and retarded neuroinvasion following intraperitoneal scrapie inoculation.

scholarly journals EPC1/TIP60-Mediated Histone Acetylation Facilitates Spermiogenesis in Mice

2017 ◽  
Vol 37 (19) ◽  
Author(s):  
Yixin Dong ◽  
Kyo-ichi Isono ◽  
Kazuyuki Ohbo ◽  
Takaho A. Endo ◽  
Osamu Ohara ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Germ Cells ◽  
Essential Role ◽  
Critical Role ◽  
Male Germ Cells ◽  
Genetic Ablation ◽  
Histone Hyperacetylation ◽  
Critical Components ◽  
Underlying Mechanisms

ABSTRACT Global histone hyperacetylation is suggested to play a critical role for replacement of histones by transition proteins and protamines to compact the genome during spermiogenesis. However, the underlying mechanisms for hyperacetylation-mediated histone replacement remains poorly understood. Here, we report that EPC1 and TIP60, two critical components of the mammalian nucleosome acetyltransferase of H4 (NuA4) complexes, are coexpressed in male germ cells. Strikingly, genetic ablation of either Epc1 or Tip60 disrupts hyperacetylation and impairs histone replacement, in turn causing aberrant spermatid development. Taking these observations together, we reveal an essential role of the NuA4 complexes for histone hyperacetylation and subsequent compaction of the spermatid genome.

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