scholarly journals Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Kirby M Donnelly ◽  
Olivia R DeLorenzo ◽  
Aprem DA Zaya ◽  
Gabrielle E Pisano ◽  
Wint M Thu ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Activity ◽  
Olfactory System ◽  
Scavenger Receptor ◽  
Protein Aggregates ◽  
Synaptic Dysfunction ◽  
Mutant Huntingtin ◽  
Neuronal Synapses ◽  
The Brain ◽  
Adult Drosophila

Emerging evidence supports the hypothesis that pathogenic protein aggregates associated with neurodegenerative diseases spread from cell to cell through the brain in a manner akin to infectious prions. Here, we show that mutant huntingtin (mHtt) aggregates associated with Huntington disease transfer anterogradely from presynaptic to postsynaptic neurons in the adult Drosophila olfactory system. Trans-synaptic transmission of mHtt aggregates is inversely correlated with neuronal activity and blocked by inhibiting caspases in presynaptic neurons, implicating synaptic dysfunction and cell death in aggregate spreading. Remarkably, mHtt aggregate transmission across synapses requires the glial scavenger receptor Draper and involves a transient visit to the glial cytoplasm, indicating that phagocytic glia act as obligatory intermediates in aggregate spreading between synaptically-connected neurons. These findings expand our understanding of phagocytic glia as double-edged players in neurodegeneration—by clearing neurotoxic protein aggregates, but also providing an opportunity for prion-like seeds to evade phagolysosomal degradation and propagate further in the brain.

scholarly journals Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses

2019 ◽  
Author(s):  
Kirby M. Donnelly ◽  
Olivia R. DeLorenzo ◽  
Aprem D.A. Zaya ◽  
Gabrielle E. Pisano ◽  
Wint M. Thu ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Activity ◽  
Huntington Disease ◽  
Olfactory System ◽  
Scavenger Receptor ◽  
Protein Aggregates ◽  
Synaptic Dysfunction ◽  
Mutant Huntingtin ◽  
Neuronal Synapses ◽  
The Brain

ABSTRACTEmerging evidence supports the hypothesis that pathogenic protein aggregates associated with neurodegenerative diseases spread from cell to cell through the brain in a manner akin to infectious prions. Here, we show that mutant huntingtin (mHtt) aggregates associated with Huntington disease transfer anterogradely from presynaptic to postsynaptic neurons in the adult Drosophila olfactory system. Trans-synaptic transmission of mHtt aggregates is inversely correlated with neuronal activity and blocked by inhibiting caspases in presynaptic neurons, implicating synaptic dysfunction and cell death in aggregate spreading. Remarkably, mHtt aggregate transmission across synapses requires the glial scavenger receptor Draper and involves a transient visit to the glial cytoplasm, indicating that phagocytic glia act as obligatory intermediates in aggregate spreading between synaptically-connected neurons. These findings expand our understanding of phagocytic glia as double-edged players in neurodegeneration—by clearing neurotoxic protein aggregates, but also providing an opportunity for prion-like seeds to evade phagolysosomal degradation and propagate further in the brain.

scholarly journals Mutant huntingtin reduces vesicular zinc level by inhibiting the binding of Sp1 to ZnT3 promoter

2020 ◽  
Author(s):  
Li Niu ◽  
Shiming Yang ◽  
Weixi Wang ◽  
Cui-fang Ye ◽  
He Li
Keyword(s):  
Molecular Mechanisms ◽  
Early Stage ◽  
Brain Regions ◽  
Zinc Level ◽  
Significant Loss ◽  
Zinc Homeostasis ◽  
Synaptic Dysfunction ◽  
Mutant Huntingtin ◽  
Bhk Cells ◽  
The Brain

Abstract Background Synaptic dysfunction caused by mutant huntingtin greatly contributes to Huntington’s disease (HD) pathogenesis. HD patients show cognitive impairment as well as uncontrolled movements. Vesicular zinc is closely linked to modulating synaptic transmission and maintaining cognitive ability. However, whether does mutant huntingtin affect zinc homeostasis in the brain or not? This will be of great significance for further revealing the pathogenesis of HD. Methods N171-HD82Q transgenic mice and cultured BHK cells expressing N-terminal mutant huntingtin fragment containing 160 glutamines (160Q BHK cells) were used to investigate the effect of mutant huntingtin on zinc homeostasis and its molecular mechanisms. Results Herein, we have demonstrated that the density of synaptic vesicular zinc decreases in the cortex, striatum and hippocampus of N171-82Q mice. Given that vesicular zinc concentration depends on the abundance of zinc transporter 3 (ZnT3) on the membrane of synaptic vesicles, ZnT3 expression is detected in the brain of N171-82Q mice and 160Q BHK cells. Mutant huntingtin leads to a dramatical decrease in ZnT3 mRNA and protein levels in the three brain regions of these mice aged from 14 to 20 weeks. Significantly, Sp1 activates ZnT3 transcription via its binding to the GC boxes in ZnT3 promoter. Nevertheless, mutant huntingtin inhibits the binding of Sp1 to the promoter of ZnT3 gene and down-regulates ZnT3 expression. Furthermore, the overexpression of Sp1 ameliorates inhibition of ZnT3 gene transcription by mutant huntingtin. Conclusions Collectively, this first study to reveal a significant loss of synaptic vesicular zinc and ZnT3 expression caused by mutant huntingtin in the early stage of HD. Our findings have revealed the molecular mechanism underlying this change. Mutant huntingtin inhibits the binding of Sp1 to ZnT3 gene promoter to reduce ZnT3 expression. The imbalance of vesicular zinc homeostasis may be closely associated with synaptic dysfunction and cognitive deficits in HD. This work sheds novel mechanistic insights into the pathogenesis of HD and promises a potential therapeutic strategy for HD.

scholarly journals Olfactory neuron turnover in adult Drosophila

2020 ◽  
Author(s):  
Ismael Fernández-Hernández ◽  
Eric Hu ◽  
Michael A. Bonaguidi
Keyword(s):  
Sensory Neurons ◽  
Olfactory Epithelium ◽  
Olfactory System ◽  
Lineage Tracing ◽  
Olfactory Neuron ◽  
Neuronal Regeneration ◽  
Continuous Generation ◽  
The Brain ◽  
Adult Drosophila ◽  
Tracing Method

ABSTRACTSustained neurogenesis occurs in the olfactory epithelium of several species, including humans, to support olfactory function throughout life. We recently developed a modified lineage tracing method to identify adult neurogenesis in Drosophila. By applying this technique, here we report on the continuous generation of Olfactory Sensory Neurons (OSN) in the antennae of adult Drosophila. New neurons develop sensory dendrites and project axons targeting diverse glomeruli of the antennal lobes in the brain. Furthermore, we identified sustained apoptosis of OSN in the antennae of adult flies, revealing unexpected turnover in the adult olfactory system. Our results substantiate Drosophila as a compelling platform to expedite research about mechanisms and compounds promoting neuronal regeneration, circuit remodeling and its contribution to behavior in the adult.

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 Optineurin promotes aggregation of mutant huntingtin and mutant ataxin-3, and reduces cytotoxicity of aggregates

2020 ◽  
Author(s):  
Shivranjani C Moharir ◽  
Akhouri Kishore Raghawan ◽  
Ghanshyam Swarup
Keyword(s):  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Neuronal Cells ◽  
Protein Aggregates ◽  
Mutant Protein ◽  
Mutant Huntingtin ◽  
Aggregate Formation ◽  
Wild Type ◽  
Mutant Proteins

AbstractOptineurin (OPTN), a cytoplasmic adaptor protein involved in cargo selective autophagy of bacteria, damaged mitochondria and mutant protein aggregates, is frequently seen in pathological structures containing protein aggregates, associated with several neurodegenerative diseases. However, the function of OPTN in these protein aggregates is not known. Here, we have explored the role of OPTN in mutant protein aggregation and in cytoprotection from toxicity of mutant proteins. Mutant huntingtin (mHtt) and mutant ataxin-3 (mAtax-3) showed reduced formation of aggregates in Optn−/− mouse embryonic fibroblasts as compared with wild type cells. Co-expression of OPTN enhanced aggregate formation by mHtt and mAtax-3 in Optn−/− cells. C-terminal domain of OPTN (412-577 amino acids) was necessary and sufficient to promote aggregate formation by these mutant proteins. The E478G mutant of OPTN, defective in ubiquitin-binding and autophagy, was also able to promote aggregation of mHtt and mAtax-3. OPTN and its C-terminal domain form a complex with the chaperone HSP70 known to promote mutant protein aggregation. Overexpression of mHtt or mAtax-3 induced more cell death in Optn−/− cells compared with wild type cells. Importantly, compared to wild type cells, Optn-deficient cells having mHtt or mAtax-3 aggregates showed higher level of cell death in neuronal (N2A) and non-neuronal cells. Our results show that OPTN promotes formation of mutant huntingtin and mutant ataxin-3 aggregates, and this function of OPTN might be mediated through interaction with HSP70 chaperones. Our results also show that OPTN reduces cytotoxicity caused by these mutant protein aggregates.Significance statementThe hallmark of several neurodegenerative diseases like amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, Alzheimer’s disease and Pick’s disease is the formation of pathological structures containing aggregated proteins, and OPTN is frequently observed in these structures. What role optineurin plays in those aggregates is not clear. Our results show that OPTN promotes aggregation of mutant huntingtin and mutant ataxin-3, and reduces cytotoxicity of aggregates in neuronal and non-neuronal cells. We suggest that OPTN provides cytoprotection in three different ways-by promoting mutant protein aggregation, by reducing cytotoxicity of aggregates and by autophagy-dependent clearance of aggregates reported earlier. These properties of OPTN provide a possible explanation for its association with various pathological structures containing protein aggregates seen in several neurodegenerative diseases.

scholarly journals Regulation of Blos1 by IRE1 prevents the accumulation of Huntingtin protein aggregates

2021 ◽  
Author(s):  
Donghwi Bae ◽  
Rachel Elizabeth Jones ◽  
Julie Hollien
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Huntington's Disease ◽  
Cultured Cells ◽  
Protein Aggregates ◽  
Mutant Huntingtin ◽  
Microtubule Organizing Center ◽  
Huntingtin Protein ◽  
Late Endosomes ◽  
Organizing Center

Huntington's Disease is characterized by accumulation of the aggregation-prone mutant Huntingtin (mHTT) protein. Here, we show that expression of mHTT in mouse cultured cells activates IRE1, the transmembrane sensor of stress in the endoplasmic reticulum, leading to degradation of the Blos1 mRNA and repositioning of lysosomes and late endosomes toward the microtubule organizing center. Overriding Blos1 degradation results in accumulation of larger mHTT aggregates and increased cell death. Although mHTT is degraded by macroautophagy when highly expressed, we show that prior to the formation of large aggregates, mHTT is degraded via an ESCRT-dependent, endosomal microautophagy pathway. This pathway is enhanced by Blos1 degradation and appears to protect cells from a toxic, less aggregated form of mHTT.

Biological response of the organism to the introduction of metal nanocomposites

2020 ◽  
pp. 761-762
Author(s):  
L. M. Sosedova ◽  
V. S. Rukavishnikov ◽  
E. A. Titov
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Biological Response ◽  
Brain Cell ◽  
Metal Nanocomposites ◽  
The Brain

The results of a study on rats toxicity of nanoparticles of metals bismuth, gadolinium and silver encapsulated in a natural biopolymer matrix arabinogalactan are presented. When intake of nanocomposite of silver revealed the readiness of the brain cell to apoptosis. The effect of bismuth and gadolinium nanocomposites did not cause an increase in the process of programmed cell death.

scholarly journals Age influences susceptibility of brain capillary endothelial cells to La Crosse virus infection and cell death

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Rahul Basu ◽  
Vinod Nair ◽  
Clayton W. Winkler ◽  
Tyson A. Woods ◽  
Iain D. C. Fraser ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Virus Infection ◽  
La Crosse Virus ◽  
Brain Capillary ◽  
Adult Mice ◽  
Age Related ◽  
Capillary Endothelial Cells ◽  
The Brain

Abstract Background A key factor in the development of viral encephalitis is a virus crossing the blood-brain barrier (BBB). We have previously shown that age-related susceptibility of mice to the La Crosse virus (LACV), the leading cause of pediatric arbovirus encephalitis in the USA, was associated with the ability of the virus to cross the BBB. LACV infection in weanling mice (aged around 3 weeks) results in vascular leakage in the olfactory bulb/tract (OB/OT) region of the brain, which is not observed in adult mice aged > 6–8 weeks. Thus, we studied age-specific differences in the response of brain capillary endothelial cells (BCECs) to LACV infection. Methods To examine mechanisms of LACV-induced BBB breakdown and infection of the CNS, we analyzed BCECs directly isolated from weanling and adult mice as well as established a model where these cells were infected in vitro and cultured for a short period to determine susceptibility to virus infection and cell death. Additionally, we utilized correlative light electron microscopy (CLEM) to examine whether changes in cell morphology and function were also observed in BCECs in vivo. Results BCECs from weanling, but not adult mice, had detectable infection after several days in culture when taken ex vivo from infected mice suggesting that these cells could be infected in vitro. Further analysis of BCECs from uninfected mice, infected in vitro, showed that weanling BCECs were more susceptible to virus infection than adult BCECs, with higher levels of infected cells, released virus as well as cytopathic effects (CPE) and cell death. Although direct LACV infection is not detected in the weanling BCECs, CLEM analysis of brain tissue from weanling mice indicated that LACV infection induced significant cerebrovascular damage which allowed virus-sized particles to enter the brain parenchyma. Conclusions These findings indicate that BCECs isolated from adult and weanling mice have differential viral load, infectivity, and susceptibility to LACV. These age-related differences in susceptibility may strongly influence LACV-induced BBB leakage and neurovascular damage allowing virus invasion of the CNS and the development of neurological disease.

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