Motor Neuron Disease-Associated Mutant Vesicle-Associated Membrane Protein-Associated Protein (VAP) B Recruits Wild-Type VAPs into Endoplasmic Reticulum-Derived Tubular Aggregates

To examine the mechanism through which neurofilaments regulate the caliber of myelinated axons and to test how aberrant accumulations of neurofilaments cause motor neuron disease, mice have been constructed that express wild-type mouse NF-H up to 4.5 times the normal level. Small increases in NF-H expression lead to increased total neurofilament content and larger myelinated axons, whereas larger increases in NF-H decrease total neurofilament content and strongly inhibit radial growth. Increasing NF-H expression selectively slow neurofilament transport into and along axons, resulting in severe perikaryal accumulation of neurofilaments and proximal axonal swellings in motor neurons. Unlike the situation in transgenic mice expressing modest levels of human NF-H (Cote, F., J.F. Collard, and J.P. Julien. 1993. Cell. 73:35-46), even 4.5 times the normal level of wild-type mouse NF-H does not result in any overt phenotype or enhanced motor neuron degeneration or loss. Rather, motor neurons are extraordinarily tolerant of wild-type murine NF-H, whereas wild-type human NF-H, which differs from the mouse homolog at > 160 residue positions, mediates motor neuron disease in mice by acting as an aberrant, mutant subunit.

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The effect of mild traumatic brain injury on peripheral nervous system pathology in wild-type mice and the G93A mutant mouse model of motor neuron disease

Neuroscience ◽

10.1016/j.neuroscience.2015.04.041 ◽

2015 ◽

Vol 298 ◽

pp. 410-423 ◽

Cited By ~ 10

Author(s):

T.M. Evans ◽

C.A. Jaramillo ◽

K. Sataranatarajan ◽

L. Watts ◽

M. Sabia ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Nervous System ◽

Brain Injury ◽

Mouse Model ◽

Motor Neuron ◽

Motor Neuron Disease ◽

Peripheral Nervous System ◽

Mild Traumatic Brain Injury ◽

Mutant Mouse ◽

Wild Type

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ALS-Associated Endoplasmic Reticulum Proteins in Denervated Skeletal Muscle: Implications for Motor Neuron Disease Pathology

Brain Pathology ◽

10.1111/bpa.12453 ◽

2017 ◽

Vol 27 (6) ◽

pp. 781-794 ◽

Cited By ~ 12

Author(s):

C. M. Jesse ◽

E. Bushuven ◽

P. Tripathi ◽

A. Chandrasekar ◽

C. M. Simon ◽

...

Keyword(s):

Skeletal Muscle ◽

Endoplasmic Reticulum ◽

Motor Neuron ◽

Motor Neuron Disease ◽

Endoplasmic Reticulum Proteins

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Are Bunina Bodies of Endoplasmic Reticulum Origin? An Ultrastructural Study of Subthalamic Eosinophilic Inclusions in a Case of Atypical Motor Neuron Disease

Pathology International ◽

10.1111/j.1440-1827.1991.tb01634.x ◽

1991 ◽

Vol 41 (12) ◽

pp. 889-894 ◽

Cited By ~ 1

Author(s):

Hitoshi Takahashi ◽

Eisaku Ohama ◽

Fusahiro Ikuta

Keyword(s):

Endoplasmic Reticulum ◽

Motor Neuron ◽

Motor Neuron Disease ◽

Ultrastructural Study ◽

Bunina Bodies ◽

Eosinophilic Inclusions

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N88S seipin mutant transgenic mice develop features of seipinopathy/BSCL2-related motor neuron disease via endoplasmic reticulum stress

Human Molecular Genetics ◽

10.1093/hmg/ddr304 ◽

2011 ◽

Vol 20 (19) ◽

pp. 3831-3840 ◽

Cited By ~ 36

Author(s):

Takuya Yagi ◽

Daisuke Ito ◽

Yoshihiro Nihei ◽

Tadayuki Ishihara ◽

Norihiro Suzuki

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Transgenic Mice ◽

Motor Neuron ◽

Motor Neuron Disease

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ER-phagy requires Lnp1, a protein that stabilizes rearrangements of the ER network

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1805032115 ◽

2018 ◽

Vol 115 (27) ◽

pp. E6237-E6244 ◽

Cited By ~ 17

Author(s):

Shuliang Chen ◽

Yixian Cui ◽

Smriti Parashar ◽

Peter J. Novick ◽

Susan Ferro-Novick

Keyword(s):

Endoplasmic Reticulum ◽

Membrane Protein ◽

Scaffold Protein ◽

Cell Cortex ◽

Wild Type ◽

Autophagosome Formation ◽

Cell Interior ◽

Rapamycin Treatment ◽

Selective Autophagy ◽

Latrunculin A

The endoplasmic reticulum (ER) forms a contiguous network of tubules and sheets that is predominantly associated with the cell cortex in yeast. Upon treatment with rapamycin, the ER undergoes degradation by selective autophagy. This process, termed ER-phagy, requires Atg40, a selective autophagy receptor that localizes to the cortical ER. Here we report that ER-phagy also requires Lnp1, an ER membrane protein that normally resides at the three-way junctions of the ER network, where it serves to stabilize the network as it is continually remodeled. Rapamycin treatment increases the expression of Atg40, driving ER domains marked by Atg40 puncta to associate with Atg11, a scaffold protein needed to form autophagosomes. Although Atg40 largely localizes to the cortical ER, the autophagy machinery resides in the cell interior. The localization of Atg40 to sites of autophagosome formation is blocked in an lnp1Δ mutant or upon treatment of wild-type cells with the actin-depolymerizing drug Latrunculin A. This prevents the association of Atg40 with Atg11 and the packaging of the ER into autophagosomes. We propose that Lnp1 is needed to stabilize the actin-dependent remodeling of the ER that is essential for ER-phagy.

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Correction of delF508-CFTR activity with benzo(c)quinolizinium compounds through facilitation of its processing in cystic fibrosis airway cells

Journal of Cell Science ◽

10.1242/jcs.114.22.4073 ◽

2001 ◽

Vol 114 (22) ◽

pp. 4073-4081

Author(s):

Robert L. Dormer ◽

Renaud Dérand ◽

Ceinwen M. McNeilly ◽

Yvette Mettey ◽

Laurence Bulteau-Pignoux ◽

...

Keyword(s):

Cystic Fibrosis ◽

Endoplasmic Reticulum ◽

Membrane Protein ◽

Protein Trafficking ◽

Apical Region ◽

Major Advance ◽

Wild Type ◽

Cl Transport ◽

Airway Cells

A number of genetic diseases, including cystic fibrosis, have been identified as disorders of protein trafficking associated with retention of mutant protein within the endoplasmic reticulum. In the presence of the benzo(c)quinolizinium drugs, MPB-07 and its congener MPB-91, we show the activation of cystic fibrosis transmembrane conductance regulator (CFTR) delF508 channels in IB3-1 human cells, which express endogenous levels of delF508-CFTR. These drugs were without effect on the Ca2+-activated Cl– transport, whereas the swelling-activated Cl– transport was found altered in MPB-treated cells. Immunoprecipitation and in vitro phosphorylation shows a 20% increase of the band C form of delF508 after MPB treatment. We then investigated the effect of these drugs on the extent of mislocalisation of delF508-CFTR in native airway cells from cystic fibrosis patients. We first showed that delF508 CFTR was characteristically restricted to an endoplasmic reticulum location in approximately 80% of untreated cells from CF patients homozygous for the delF508-CFTR mutation. By contrast, 60-70% of cells from non-CF patients showed wild-type CFTR in an apical location. MPB-07 treatment caused dramatic relocation of delF508-CFTR to the apical region such that the majority of delF508/delF508 CF cells showed a similar CFTR location to that of wild-type. MPB-07 had no apparent effect on the distribution of wild-type CFTR, the apical membrane protein CD59 or the ER membrane Ca2+,Mg-ATPase. We also showed a similar pharmacological effect in nasal cells freshly isolated from a delF508/G551D CF patient. The results demonstrate selective redirection of a mutant membrane protein using cell-permeant small molecules of the benzo(c)quinolizinium family and provide a major advance towards development of a targetted drug treatment for cystic fibrosis and other disorders of protein trafficking.

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Sarcolipin alters SERCA1a interdomain communication by impairing binding of both calcium and ATP

Scientific Reports ◽

10.1038/s41598-021-81061-6 ◽

2021 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Cédric Montigny ◽

Dong Liang Huang ◽

Veronica Beswick ◽

Thomas Barbot ◽

Christine Jaxel ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Membrane Protein ◽

Functional Role ◽

Published Data ◽

Allosteric Effect ◽

Transport Activity ◽

Wild Type ◽

Experimental Conditions ◽

Interdomain Communication

AbstractSarcolipin (SLN), a single-spanning membrane protein, is a regulator of the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA1a). Chemically synthesized SLN, palmitoylated or not (pSLN or SLN), and recombinant wild-type rabbit SERCA1a expressed in S. cerevisiae design experimental conditions that provide a deeper understanding of the functional role of SLN on the regulation of SERCA1a. Our data show that chemically synthesized SLN interacts with recombinant SERCA1a, with calcium-deprived E2 state as well as with calcium-bound E1 state. This interaction hampers the binding of calcium in agreement with published data. Unexpectedly, SLN has also an allosteric effect on SERCA1a transport activity by impairing the binding of ATP. Our results reveal that SLN significantly slows down the E2 to Ca2.E1 transition of SERCA1a while it affects neither phosphorylation nor dephosphorylation. Comparison with chemically synthesized SLN deprived of acylation demonstrates that palmitoylation is not necessary for either inhibition or association with SERCA1a. However, it has a small but statistically significant effect on SERCA1a phosphorylation when various ratios of SLN-SERCA1a or pSLN-SERCA1a are tested.

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