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.

scholarly journals The pathobiology of perturbed mutant huntingtin protein–protein interactions in Huntington's disease

2019 ◽  
Vol 151 (4) ◽  
pp. 507-519 ◽  
Author(s):  
Erich E. Wanker ◽  
Anne Ast ◽  
Franziska Schindler ◽  
Philipp Trepte ◽  
Sigrid Schnoegl
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein Interactions ◽  
Mutant Huntingtin ◽  
Protein Protein Interactions ◽  
Huntingtin Protein ◽  
Mutant Huntingtin Protein

scholarly journals Degradation of Blos1 mRNA by IRE1 repositions lysosomes and protects cells from stress

2019 ◽  
Vol 218 (4) ◽  
pp. 1118-1127 ◽  
Author(s):  
Donghwi Bae ◽  
Kristin A. Moore ◽  
Jessica M. Mella ◽  
Samantha Y. Hayashi ◽  
Julie Hollien
Keyword(s):  
Protein Aggregates ◽  
Stress Sensitivity ◽  
Microtubule Organizing Center ◽  
Endosomal Sorting ◽  
Unfolded Protein ◽  
Organizing Center ◽  
Specific Mrnas ◽  
Response To Stress ◽  
Lysosome Related Organelles ◽  
Protein Response

Cells respond to stress in the ER by initiating the widely conserved unfolded protein response. Activation of the ER transmembrane nuclease IRE1 leads to the degradation of specific mRNAs, but how this pathway affects the ability of cells to recover from stress is not known. Here, we show that degradation of the mRNA encoding biogenesis of lysosome-related organelles 1 subunit 1 (Blos1) leads to the repositioning of late endosomes (LEs)/lysosomes to the microtubule-organizing center in response to stress in mouse cells. Overriding Blos1 degradation led to ER stress sensitivity and the accumulation of ubiquitinated protein aggregates, whose efficient degradation required their independent trafficking to the cell center and the LE-associated endosomal sorting complexes required for transport. We propose that Blos1 regulation by IRE1 promotes LE-mediated microautophagy of protein aggregates and protects cells from their cytotoxic effects.

Distinct aggregation and cell death patterns among different types of primary neurons induced by mutant huntingtin protein

2004 ◽  
Vol 89 (4) ◽  
pp. 974-987 ◽  
Author(s):  
Kazuhiko Tagawa ◽  
Masataka Hoshino ◽  
Tomohiro Okuda ◽  
Hiroko Ueda ◽  
Hiroshi Hayashi ◽  
...  
Keyword(s):  
Cell Death ◽  
Primary Neurons ◽  
Mutant Huntingtin ◽  
Huntingtin Protein ◽  
Different Types ◽  
Mutant Huntingtin Protein

scholarly journals Ultrastructural immunocytochemical localization of calmodulin in cultured cells.

1983 ◽  
Vol 31 (4) ◽  
pp. 445-461 ◽  
Author(s):  
M C Willingham ◽  
J Wehland ◽  
C B Klee ◽  
N D Richert ◽  
A V Rutherford ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Performic Acid ◽  
Microtubule Organizing Center ◽  
Interphase Cells ◽  
Organizing Center ◽  
Late Telophase ◽  
Cytoplasmic Microtubules ◽  
Spindle Microtubules ◽  
And Function ◽  
Fibroblastic Cells

Using an antibody prepared against performic acid-treated calmodulin, we have localized calmodulin in cultured fibroblastic cells by immunofluorescence and immunoelectron microscopy. In interphase cells, calmodulin was found to be diffusely distributed throughout the cytosol. An increased amount of calmodulin was found in the pericentriolar region of interphase cells. No significant aggregation of calmodulin was found in association with microfilaments, peripheral cytoplasmic microtubules or clathrin-coated structures. Calmodulin was present in moderate amounts in microvilli, ruffles, and zeiotic blebs of the cell surface. In motitic cells, calmodulin was found concentrated in the pericentriolar region, and appeared to concentrate along radiating spindle microtubules proximal to the centrioles. Redistribution of calmodulin was seen between early and late telophase, in which the pericentriolar pattern of calmodulin in early telophase shifted to an aggregation on the intercellular bridge, with a large part of the midbody portion of the bridge being devoid of calmodulin. These results show that calmodulin is distributed throughout the cytosol, but is markedly concentrated in the region of the microtubule organizing center in interphase cells, as well as in elements of the mitotic spindle apparatus. This distribution suggests that calmodulin has a regulatory role in the organization and function of microtubules during interphase, as well as during mitosis.

A protein related to brain microtubule-associated protein MAP1B is a component of the mammalian centrosome

1994 ◽  
Vol 107 (2) ◽  
pp. 601-611 ◽  
Author(s):  
J.E. Dominguez ◽  
B. Buendia ◽  
C. Lopez-Otin ◽  
C. Antony ◽  
E. Karsenti ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Cultured Cells ◽  
Polyclonal Antibodies ◽  
Microtubule Organizing Center ◽  
Microtubule Associated Proteins ◽  
Organizing Center ◽  
Associated Proteins ◽  
Pericentriolar Material ◽  
Peptide Maps

The centrosome is the main microtubule organizing center of mammalian cells. Structurally, it is composed of a pair of centrioles surrounded by a fibro-granular material (the pericentriolar material) from which microtubules are nucleated. However, the nature of centrosomal molecules involved in microtubules nucleation is still obscure. Since brain microtubule-associated proteins (MAPs) lower the critical tubulin concentration required for microtubule nucleation in tubulin solution in vitro, we have examined their possible association with centrosomes. By immunofluorescence, monoclonal and polyclonal antibodies raised against MAP1B stain the centrosome in cultured cells as well as purified centrosomes, whereas antibodies raised against MAP2 give a completely negative reaction. The MAP1B-related antigen is localized to the pericentriolar material as revealed by immunoelectron microscopy. In preparations of purified centrosomes analyzed on poly-acrylamide gels, a protein that migrates as brain MAP1B is present. After blotting on nitrocellulose, it is decorated by anti-MAP1B antibodies and the amino acid sequence of proteolytic fragments of this protein is similar to brain MAP1B. Moreover, brain MAP1B and its centrosomal counterpart share the same phosphorylation features and have similar peptide maps. These data strongly suggest that a protein homologue to MAP1B is present in centrosomes and it is a good candidate for being involved in the nucleating activity of the pericentriolar material.

Accelerating the clearance of mutant huntingtin protein aggregates through autophagy induction by europium hydroxide nanorods

Biomaterials ◽  
2014 ◽  
Vol 35 (3) ◽  
pp. 899-907 ◽  
Author(s):  
Peng-Fei Wei ◽  
Li Zhang ◽  
Susheel Kumar Nethi ◽  
Ayan Kumar Barui ◽  
Jun Lin ◽  
...  
Keyword(s):  
Protein Aggregates ◽  
Mutant Huntingtin ◽  
Huntingtin Protein ◽  
Autophagy Induction ◽  
Mutant Huntingtin Protein

Cytological variation in zoospores of Spizellomyces (Chytridiomycetes)

1984 ◽  
Vol 62 (6) ◽  
pp. 1202-1208 ◽  
Author(s):  
Donald J. S. Barr
Keyword(s):  
Endoplasmic Reticulum ◽  
Microtubule Organizing Center ◽  
Fibrillar Material ◽  
Organizing Center ◽  
Cytological Features ◽  
Cytological Characteristics

The principal cytological features and their variations are described in zoospores of 38 isolates belonging to seven species of Spizellomyces. This genus is distinguished from others in the Spizellomycetaceae by the orientation of the microtubules and the position of the nucleus relative to the kinetosome in the zoospore. Microtubules run apparently at random into the cytoplasm from a microtubule-organizing center (spur) on one side of the kinetosome. The nucleus is anteriorly or centrally positioned with a heel-like process extending to near the proximal face of the kinetosome, or it can be posteriorly positioned and elongate with one end close to the kinetosome. Differences between species are reflected by the position and shape of the nucleus, the extent of the endoplasmic reticulum which in some species circumscribes lipid globules, the presence or absence of an apparent connection by fibrillar material between the kinetosome and a nonfunctional centriole, and the morphology of the microtubule-organizing center. The zoospores of Spizellomyces punctatus (Koch) D. Barr, S. plurigibbosus (D. Barr) D. Barr, and S. palustris (Gaertner) D. Barr are cytologically similar, but those of S. acuminatus (D. Barr) D. Barr, S. dolichospermus D. Barr, S. lactosolyticus D. Barr and S. pseudodichotomus (Umphlett) D. Barr each have one or more distinctive characteristic. Spizellomyces dolichospermus and S. pseudodichotomus also have some cytological characteristics in common with the genus Kochiomyces.

scholarly journals The huntingtin inclusion is a dynamic phase-separated compartment

2019 ◽  
Vol 2 (5) ◽  
pp. e201900489 ◽  
Author(s):  
Fahmida Aktar ◽  
Chakkapong Burudpakdee ◽  
Mercedes Polanco ◽  
Sen Pei ◽  
Theresa C Swayne ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Vacuolar Membrane ◽  
Mutant Huntingtin ◽  
Small Particles ◽  
Huntingtin Protein ◽  
Disordered Protein ◽  
Dynamic Phase ◽  
Mutant Huntingtin Protein ◽  
Polyglutamine Tract

Inclusions of disordered protein are a characteristic feature of most neurodegenerative diseases, including Huntington’s disease. Huntington’s disease is caused by expansion of a polyglutamine tract in the huntingtin protein; mutant huntingtin protein (mHtt) is unstable and accumulates in large intracellular inclusions both in affected individuals and when expressed in eukaryotic cells. Using mHtt-GFP expressed in Saccharomyces cerevisiae, we find that mHtt-GFP inclusions are dynamic, mobile, gel-like structures that concentrate mHtt together with the disaggregase Hsp104. Although inclusions may associate with the vacuolar membrane, the association is reversible and we find that inclusions of mHtt in S. cerevisiae are not taken up by the vacuole or other organelles. Instead, a pulse-chase study using photoconverted mHtt-mEos2 revealed that mHtt is directly and continuously removed from the inclusion body. In addition to mobile inclusions, we also imaged and tracked the movements of small particles of mHtt-GFP and determine that they move randomly. These observations suggest that inclusions may grow through the collision and coalescence of small aggregative particles.

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