 |
21 July 2006. When it works properly, the endoplasmic reticulum (ER) constantly pumps out newly synthesized membrane proteins, perfectly folded and sorted to their proper cellular destination. At the same time, this organelle keeps cellular calcium levels in balance. But when the ER gets overloaded and stressed, the cell counters with the unfolded protein response (UPR), a pathway which results in slowed protein synthesis and enhanced chaperone production to clear the backlog. If the overload persists, as it does in many neurodegenerative diseases featuring continuous production of mutant, malshaped proteins, such as Alzheimer disease (AD), cells undergo an ER-dependent form of apoptosis (see ARF related news story).
But ER stress can also come from without, according to new work from Claudia Pereira and colleagues at the University of Coimbra in Portugal. In a paper published online July 14 in the Neurobiology of Disease, the researchers report that application of Aβ1-40 to cultured neurons causes ER stress via pathological release of intracellular calcium stores. Chronically elevated intracellular calcium then leads to oxidative stress and cytochrome c release from mitochondria, triggering caspase activation and cell death. Blocking calcium release by inhibiting ER calcium channels reverses all these effects of Aβ and rescues neurons. Their results show that ER stress, induced by Aβ added to cells, can cooperate with mitochondrial pathways to trigger cell death. The results may apply to other diseases, too, since they showed that a neurotoxic prion peptide had very similar effects.
In other news from the ER, a study from Malcolm Horne and colleagues at the University of Melbourne in Australia shows upregulation of the UPR in SOD mutant models of ALS, and suggests that increased chaperone levels may be neuroprotective. Lastly, some basic research on the UPR reminds us once again how elegantly evolution solves life and death problems like protecting ER function. Work from Jonathan Weissman’s lab at the University of California, San Francisco, reveals a third arm to the UPR—in addition to transcriptional and translational responses, the cell also initiates degradation of mRNAs that specifically code for ER-targeted proteins.
Studies on the role of ER stress in Alzheimer disease have focused mostly on the presenilin proteins (PS). FAD-causing PS mutations interfere with protein folding and sensitize cells to ER stress-induced cell death by downregulating the UPR (see ARF related news story). But there have been hints that the ER stress-induced apoptosis could be involved in Aβ toxicity. Work from Junying Yuan’s lab at Harvard University showed that neurons from caspase-12 knockout mice were resistant to ER stress-induced cell death, and also Aβ toxicity (see ARF related news story). Soluble amyloid oligomers perturb calcium homeostasis in neurons, which is another trigger of ER stress (De Muro et al., 2005).
For these reasons, Pereira’s group looked specifically for ER-mediated apoptosis in response to exogenous Aβ1-40 peptides in cultured cortical neurons. First author Elisabete Ferreiro and colleagues showed that Aβ treatment increased ER stress, as indicated by elevated protein levels of the chaperone Grp78 and caspase-12 activation. Aβ also caused a rapid (within 1 hour) and sustained (up to 48 hours) increase in intracellular calcium. The calcium was derived from ER stores, since its accumulation was blocked by inhibiting either of the two major ER calcium release channels, the ryanodine receptor (RyR) and the inositol trisphosphate receptor (IP3R), with dantrolene or xestospongin C, respectively.
High intracellular calcium can stress out mitochondria, too, and the researchers showed that Aβ caused oxidative stress and apoptosis via a mitochondrial pathway. They recorded elevated production of reactive oxygen species, cytochrome c release from mitochondria, caspase activation (including the executioner caspase, caspase-3), and cell death. All these effects were inhibited by danotrolene or xestospongin C. From this data, the authors conclude that Aβ causes significant, early release of intracellular calcium, ER stress, and activation of the mitochondrial apoptosis pathway. Their results raise the possibility that calcium release channel blockers might be useful to protect against neuron loss in AD and prion diseases.
The UPR and ER stress-induced apoptosis also figure in the death of motor neurons triggered by mutant superoxide dismutase in ALS, according to the Australian researchers. In their paper, published online July 17 in the JBC, first author Julie Atkin and coworkers show that SOD1 mutant mice upregulate several markers of the UPR, including cleaved caspases-12, -9, and -3. They also found that the ER chaperone protein disulfide isomerase (PDI) was upregulated and associated with mutant SOD1 in rodent ALS models and in cells. Inhibiting PDI increased SOD1 aggregation, suggesting that the increased PDI they observed might represent a neuroprotective response. This report jibes with a paper earlier this year from Stuart Lipton, Eliezer Masliah, and Yasuyuki Normura describing inactivation of PDI in brains of AD and PD patients and suggesting that loss of PDI activity could exacerbate the pathology of neurodegenerative diseases (see ARF related news story).
And finally, a fascinating paper in the July 7 issue of Science shows that there is more to the UPR than upregulation of chaperones. The two major effector arms of the UPR both emanate from the ER transmembrane protein IRE-1. Sensing a build-up of unfolded proteins on its luminal side, IRE-1 activates cytosolic kinase and ribonuclease activities, which upregulate chaperone production (through RNA splicing to produce transcription factors) and downregulate protein synthesis at the level of translation. The net effect is to enhance the capacity of the ER while reducing its load. Now, Julie Hollien and Jonathan S. Weissman reveal that IRE-1 activation also leads to a rapid and specific degradation of mRNAs targeted to the ER. Using its cytosolic ribonuclease activity, IRE-1 chews up the mRNAs for the nascent polypeptides it senses in the lumen of the ER. This targeted destruction gives the ER an immediate time-out from protein folding, and also allows it to accommodate the increased syntheses of chaperones that comes later in the UPR. The elegant logic of the UPR thus revealed should only increase our appreciation of and curiosity about the role of this critical homeostatic mechanism in the health and demise of neurons.—Pat McCaffrey.
References:
Ferreiro E, Resende R, Costa R, Oliveira CR, Pereira CM. An endoplasmic-reticulum-specific apoptotic pathway is involved in prion and amyloid-beta peptides neurotoxicity.
Neurobiol Dis. 2006 Jul 14; [Epub ahead of print] Abstract
Atkin JD, Farg MA, Turner BJ, Tomas D, Lysaght JA, Nunan J, Rembach A, Nagley P, Beart PM, Cheema SS, Horne MK. Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein disulfide isomerase with superoxide dismutase 1. J Biol Chem. 2006 Jul 17; [Epub ahead of print] Abstract
Hollien J, Weissman JS. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science. 2006 Jul 7;313(5783):104-7. Abstract
|
|
| |
|
Comments on News and Primary Papers |
|
|
|
|
Comment by: Massimo Tabaton
|
|
|
Submitted 24 July 2006
|
Posted 24 July 2006
|
|
|
This study shows that Aβ1-40 (as well as PrP106-126 peptide) induces ER stress, leading to apoptotic death in neurons. Previous studies have ruled out the primary role of ER stress in AD (e.g., Piccini et al., 2004). It would be interesting to ascertain if endogenous Aβ (produced through a Bri/Aβ fusion protein, e.g.) induces the same cascade of events described in the study. Then, check if Aβ1-42 has the same effects. Moreover, I would test the effect of different states of aggregation of Aβ peptides.
 View all comments by Massimo Tabaton
|
|
|
|
|
Primary Papers: An endoplasmic-reticulum-specific apoptotic pathway is involved in prion and amyloid-beta peptides neurotoxicity.
Comment by: Charles Glabe, ARF Advisor
|
|
|
Submitted 25 July 2006
|
Posted 26 July 2006
|
|
|
 I recommend this paper
|
|
|
|
|
Comment by: Jeroen Hoozemans, Wiep Scheper
|
|
|
Submitted 25 July 2006
|
Posted 26 July 2006
|
|
|
I recommend the Primary Papers
Our lab previously reported activation of the UPR in AD neurons (Hoozemans et al., 2005). In the current paper, Ferreiro et al. show induction of BiP levels, as well as decreased pro-caspase-12 levels induced by Aβ1-40. This may indicate that the ER stress response (including the apoptotic branch of the UPR) is activated directly by Aβ, and may be the cause of the UPR activation that we observe in AD neurons. However, the data obtained by Ferreiro et al. in vitro appear not to corroborate fully with observations from the actual patient material. The data presented in the Ferreiro paper suggest that apoptotic cell death is a direct consequence of Aβ-induced UPR activation, whereas we find no evidence of apoptosis in AD neurons with an activated UPR. The UPR is activated as a protective mechanism to restore ER homeostasis, and although it can result in cell death after prolonged activation, it is not necessarily a bad thing. This is in agreement with our observation that the UPR is activated relatively early in AD pathology. In this respect it would be interesting to...
Read more
View all comments by Jeroen Hoozemans
View all comments by Wiep Scheper
|
|
|
|
|
Comment by: Erik Jansson
|
|
|
Submitted 24 July 2006
|
Posted 26 July 2006
|
|
|
I recommend the Primary Papers
The research community appears to play with half a deck of cards by ignoring the role of metals, particularly aluminum in co-causation of Alzheimer dementia. Ghribi et al., in a series of studies, investigated the effect of aluminum on the endoplasmic reticulum and mitochondria, and reported that the metal caused apoptosis through changes in cytochrome c, Bcl-2 and Bax in the hippocampus of aluminum-treated rabbits. There is cross-talk between the metal and amyloid, as the two toxins bond to each other, and the metal affects processing of amyloid. The aging brain has bio-accumulated a substantial amount of aluminum by age 60. Must we now move beyond a one-dimensional view of AD to make progress? Most chronic diseases of the aging process have multiple causation.
References:
Ghribi O, DeWitt DA, Forbes MS, Herman MM, Savory J. Co-involvement of mitochondria and endoplasmic reticulum in regulation of apoptosis: changes in cytochrome c, Bcl-2 and Bax in the hippocampus of aluminum-treated rabbits.
Brain Res. 2001 Jun 8;903(1-2):66-73.
Abstract
View all comments by Erik Jansson
|
|
|
|
|
Comment by: Othman Ghribi
|
|
|
Submitted 27 July 2006
|
Posted 1 August 2006
|
|
|
In a recent review paper (Ghribi, 2006), we have addressed the role of ER in Alzheimer disease and discussed data supporting dysfunction of the ER as an early event leading to Aβ accumulation in familial AD. We have also discussed the possible role of oxidative stress and other factors as contributors in Aβ accumulation by reducing the clearance of Aβ from the endoplasmic reticulum. Our previous work (Ghribi et al., 2004; 2003) also demonstrated ER stress as a mechanism underlying exogenous Aβ neurotoxicity.
References:
Ghribi O. The role of the endoplasmic reticulum in the accumulation of beta-amyloid
peptide in Alzheimer's disease. Curr Mol Med. 2006;6(1):119-33. Review. Abstract
Ghribi O, Herman MM, Pramoonjago P, Spaulding NK, Savory J. GDNF regulates the A beta-induced endoplasmic reticulum stress response in rabbit hippocampus by inhibiting the activation of gadd 153 and the JNK and ERK kinases. Neurobiol Dis. 2004;16(2):417-27. Abstract
Ghribi O, Herman MM, Savory J. Lithium inhibits Abeta-induced stress in endoplasmic reticulum of rabbit hippocampus but does not prevent oxidative damage and tau phosphorylation. J Neurosci Res. 2003;71(6):853-62. Abstract
View all comments by Othman Ghribi
|
|
|
|
|
Comment by: Dan Lindholm
|
|
|
Submitted 29 August 2006
|
Posted 29 August 2006
|
|
|
This paper shows the involvement of calcium released from the endoplasmic reticulum (ER) in neuronal death induced by a synthetic prion peptide and by the Aβ peptide as causative agents in prion and Alzheimer diseases, respectively. The work is done using cultured cortical neurons and demonstrates a cascade of events causing neuronal demise. This pathway is triggered by elevated calcium that can be blocked by inhibition of ER calcium channels.
Calcium dysregulations have long been considered as a part of neuronal toxicity in AD, as also shown by mutations in presenilins. Likewise, infected cells in prion disease show calcium elevation but the mechanisms causing cell death have remained elusive. This paper shows a possible mechanism by which disturbed calcium regulation causes cell death through a crosstalk between the ER and mitochondria leading ultimately to caspase activation. The paper is highly recommended.
View all comments by Dan Lindholm
|
|
|
|
Comments on Related Papers |
|
|
|
|
Related Paper: Disturbed activation of endoplasmic reticulum stress transducers by familial Alzheimer's disease-linked presenilin-1 mutations.
Comment by: Benjamin Wolozin, ARF Advisor (Disclosure)
|
|
|
I recommend this paper
The ER appears to be a critical site for stress in neurodegenerative diseases. Several of the proteins that are implicated in neurodegenerative disease are present in the ER, and affect ER stress responses. Our understanding of the mechanism by which proteins, such as PS1, affect ER stress signaling could provide important insights into understanding the mechanism of disease.
View all comments by Benjamin Wolozin
|
|
|
|
|
Related Paper: Disturbed activation of endoplasmic reticulum stress transducers by familial Alzheimer's disease-linked presenilin-1 mutations.
Comment by: Eddie Koo, ARF Advisor
|
|
|
I recommend this paper
Still more confusion about the upr and presenilins. Initial defects in upr reported for presenilins not confirmed by Thinakaran lab.
View all comments by Eddie Koo
|
|
|
|
Comments on Related News |
|
|
|
|
Related News: Salubrinal to the Rescue? New Compound Fights ER Stress
Comment by: Massimo Tabaton
|
|
|
Submitted 11 February 2005
|
Posted 11 February 2005
|
|
|
This is a very interesting paper. Boyce and
colleagues showed that pharmacological inhibition of dephosphorylation of eukaryotic initiator factor 2α increases its activity, thus protecting against the effects of ER stress. They also demonstrated that this effect slows down HSV replication.
However, these important findings do not seem to have a direct application in Alzheimer disease. ER stress, and the consequent UPR, are not implicated in β amyloid production, or in APP processing, as shown by my and other's groups (Siman et al, JBC, 2001; Piccini et al, Neurobiology of disease, 2004). Instead, inhibition of the effects of ER stress may be potentially beneficial in neurodegenerative disorders characterized by intracellular toxic aggregates, such as Parkinson disease and tauopathies, in which ER stress may contribute to the creation of misfolded peptides.
View all comments by Massimo Tabaton
|
|
|
|
|
Related News: Presenilins Open Escape Hatch for ER Calcium
Comment by: Humbert De Smedt
|
|
|
Submitted 14 September 2006
|
Posted 14 September 2006
|
|
|
Comment from H. De Smedt and the IP3-team in Leuven
Discrepancies in Two Recent Papers on ER Ca2+-leak Channels in Presenilin1, -2 Double Knockout Cells
This paper describes presenilin (PS)-related mechanisms that affect Ca2+ leak from the endoplasmic reticulum (ER). However, it points to a very different mechanism—Ca2+-channel leak properties of presenilin—to that which we have recently published: upregulation of type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) (Kasri et al., 2006). Although these two conclusions are not mutually exclusive, the niggling point is that both papers report very different and even sometimes opposing experimental findings. There is no obvious explanation for these discrepancies, but it is clear that all methodologies currently applied to evaluate ER Ca2+ concentrations and ER Ca2+ leak are imperfect and often lead to contradictory results. This was extensively discussed by Clark Distelhorst and Gordon Shore in their recent review of the conflicting findings...
Read more
View all comments by Humbert De Smedt
|
|
|
|
|
Related News: Presenilins Open Escape Hatch for ER Calcium
Comment by: Grace (Beth) Stutzmann
|
|
|
Submitted 14 September 2006
|
Posted 14 September 2006
|
|
|
This recent study by Tu et al. (2006) provides a much-needed advance toward understanding how presenilin (PS) mutations can alter ER Ca2+ signaling patterns. Cumulative data over the past several years have clearly shown that cells (both neurons and non-neuronal model systems) display marked increases in evoked Ca2+ release from the ER. However, the mechanism by which presenilin can influence Ca2+ stores has remained utterly elusive. An inherent hurdle has been the level at which the previous studies have been conducted: examining individual ER channel activity in biological preparations such as cell cultures and brain slices is rather intractable (with the exception of work from Kevin Foskett’s lab), while the biochemical and molecular biological approaches are too minimalist.
The planar lipid bilayer approach was, therefore, an ideal preparation to start addressing presenilin function in membranes and its relation to the Ca2+ signaling dysregulation seen with certain AD-linked presenilin mutations. This technique allows one to insert specific channels of interest into a...
Read more
View all comments by Grace (Beth) Stutzmann
|
|
|
|
|
Related News: Presenilins Open Escape Hatch for ER Calcium
Comment by: Giuliano Binetti, Cristina Fasolato, Roberta Ghidoni, Paola Pizzo, Sandro Sorbi
|
|
|
Submitted 15 September 2006
|
Posted 18 September 2006
|
|
|
The work by Bezprozvanny and colleagues is unquestionably a breath of fresh air in the field of AD, especially for those interested in the “Ca2+ overload” hypothesis for the pathogenesis of this devastating disease. It is particularly interesting given that an increasing number of groups are beginning to address this issue from the point of view of the internal stores. In fact, up until now only two papers focused the reader’s attention on Ca2+ levels inside the stores using direct approaches: one mentioned by Bezprozvanny and colleagues (Kasri et al., 2006), and one coming from our group (Zatti et al., 2006), which was not mentioned. These two papers, however, show results which need to be considered in a open discussion on the Cell’s paper.
The first finding obtained by Bezprozvanny and colleagues, showing that PSs are leak channels, does not contradict our published data: we have repeatedly demonstrated that overexpression of wt-PS2 and, to a lesser extent, also of wt-PS1, reduces the ER Ca2+ level in different cell models (Zatti et al., 2004; Giacomello et al., 2005;...
Read more
View all comments by Giuliano Binetti
View all comments by Cristina Fasolato
View all comments by Roberta Ghidoni
View all comments by Paola Pizzo
View all comments by Sandro Sorbi
|
|
|
|
|
Related News: Presenilins Open Escape Hatch for ER Calcium
Comment by: Steven Brenner
|
|
|
Submitted 18 September 2006
|
Posted 19 September 2006
|
|
|
I recommend the Primary Papers
I was quite interested in the regulation of calcium within the endoplasmic reticulum, and subsequent cell death apparently related to calcium toxicity. It appears the presenilin1 and 2 permit calcium regulation, and familial Alzheimer presenilin1 and 2 are not able to perform this function, probably leading to cell dysfunction and development of familial Alzheimer disease. This certainly is a lead to follow in determining the pathophysiology of sporadic Alzheimer disease. There may be multiple causes of endoplasmic reticulum dysfunction and calcium accumulation.
I performed aluminum neurotoxicity experiments on hippocampal rat neurons several years ago and found dantrolene and dimethylsulfoxide reduced cell death from aluminum toxicity, indicating aluminum toxicity may be mediated through release of calcium from intracellular stores and oxidative stress (1).
There may be multiple mechanisms disrupting calcium metabolism in the endoplasmic reticulum, including metals such as aluminum and other metals potentially capable of oxidation such as copper and iron. Oxidative...
Read more
View all comments by Steven Brenner
|
|
|
|
|
Related News: Presenilins Open Escape Hatch for ER Calcium
Comment by: Natalia Prevarskaya
|
|
|
Submitted 20 September 2006
|
Posted 20 September 2006
|
|
|
Presenilin Is a New Endoplasmic Reticulum Membrane Protein Essential for Calcium Leak
A long-standing mystery in the cell biology of calcium homeostasis is the molecular nature and the physiological role of “leak-channels” in the endoplasmic reticulum (ER) membrane. Indeed, the ER is the major calcium store, and the Ca2+ filling status of the ER controls many physiological processes ranging from gene expression to apoptosis and proliferation. Furthermore, more and more papers suggest that the abnormal luminal ER calcium concentration ([Ca2+]L) and deranged calcium signaling are associated with severe human pathologies such as cancer and neurodegenerative diseases.
Under resting conditions, steady-state [Ca2+]L is determined by the dynamic equilibrium of two components: an active Ca2+ uptake mediated by ATP-dependent Ca2+ pumps of the SERCA family and passive Ca2+ efflux via leak channels. Even though this pump-leak cycle appears to be a common property of Ca2+-storing organelles, little is known about the proteins controlling the Ca2+ leak pathway. Several...
Read more
View all comments by Natalia Prevarskaya
|
|
|
|
|
Related News: Presenilins Open Escape Hatch for ER Calcium
Comment by: Ilya Bezprozvanny
|
|
|
Submitted 22 September 2006
|
Posted 27 September 2006
|
|
|
I recommend the Primary Papers
Reply to Giuliano Binetti, Cristina Fasolato, Roberta Ghidoni, Paola Pizzo, and Sandro Sorbi
We are thankful to Giuliano Binetti and his colleagues for the high praise given our paper and for their insightful comments. We apologize for not discussing their highly relevant paper, Zatti et al., 2006 [1], which appeared while our manuscript was in the final stages of review and we did not see it prior to publication of our paper.
Binetti and colleagues raise interesting questions about the effects of presenilin FAD mutations on ER Ca2+ content and on inositol trisphosphate receptor (InsP3R)-mediated Ca2+ release. We attempted to reconcile our results with that of Zatti at al.; however, we ran into significant difficulties in interpreting their data.
Let us consider an example of two PS1 FAD mutants for which extensive datasets are available from several laboratories. Zatti et al. reported that expression of PS1-M146L resulted in reduced Ca2+ response to cyclopiazonic acid (CPA) + histamine (Fig. 1C), no change in response to CPA + bradykinin (BK) (Fig. 1B), ...
Read more
View all comments by Ilya Bezprozvanny
|
|
|
|
|
Related News: Presenilins Open Escape Hatch for ER Calcium
Comment by: Massimo Stefani
|
|
|
Submitted 25 September 2006
|
Posted 27 September 2006
|
|
|
I recommend the Primary Papers
The work by Bezprozvanny and colleagues undoubtedly adds considerably new information about the physiological function of presenilins as well as on their possible roles in AD pathogenesis at the molecular level. These data also add knowledge on the relationship among ER stress, presenilins, Aβ peptides, and derangement of calcium homeostasis in AD.
In my opinion, the research by Bezprozvanny and colleagues emphasizes the importance of the fundamental role of free calcium modifications in cells undergoing biochemical changes underlying AD. While not questioning the key role of Aβ peptides in this disease, the data add another possible dimension to the key role performed by calcium in cellular stress and death following the biochemical modifications characterizing AD. Hence, some presenilin mutations affecting γ-secretase activity can impair cell viability by increasing Aβ peptide production or by shifting the latter towards the more amyloidogenic Aβ42, resulting in Aβ oligomerization and cell membrane(s) permeabilization. Other mutations that do...
Read more
View all comments by Massimo Stefani
|
|
|
|
|
Related News: Less VAPid Now: Role for ALS Protein Gets Substance
Comment by: Giuseppa Pennetta
|
|
|
Submitted 26 June 2008
|
Posted 26 June 2008
|
|
|
VAPs (VAMP/synaptobrevin associated proteins) are evolutionarily conserved proteins comprising an amino-terminal domain with significant homology to the major sperm proteins (MSPs), a central coiled-coil domain, and a membrane anchor at the carboxy-terminal domain. MSPs are the most abundant proteins in the amoeboid nematode sperm, where they perform both cytoskeletal and signaling functions. In C. elegans, MSPs signal by antagonizing ephrin/Eph receptor pathway to promote oocyte meiotic maturation, ovarian sheath cell contraction, and oocyte microtubule reorganization. In 2004, Nishimura et al. reported a mutation substituting a conserved proline with a serine in a Brazilian family affected by a heterogenous group of motor neuron diseases ranging from amyotrophic lateral sclerosis (ALS) to atypical ALS and spinal muscular atrophy (1). In Drosophila, dVAP modulates number and size of boutons at neuromuscular junctions (2). Loss of function in dVAP disrupts microtubule cytoskeleton and causes an increase in miniature excitatory post-synaptic potentials that...
Read more
View all comments by Giuseppa Pennetta
|
|
|
|
|
Related News: Less VAPid Now: Role for ALS Protein Gets Substance
Comment by: John Landers
|
|
|
Submitted 15 July 2008
|
Posted 15 July 2008
|
|
|
I recommend the Primary Papers
Amyotrophic lateral sclerosis is an age-dependent, degenerative disorder of motor neurons that typically develops in the sixth decade and is uniformly fatal, usually within five years. About 10 percent of ALS cases are familial; 20 percent of these are caused by mutations in the gene encoding copper/zinc superoxide dismutase 1 (SOD1). More recently, it has been shown that mutations in the TDP-43 gene are also causative for familial ALS (1-3). The VAPB P56S mutation was originally observed in a large Brazilian family of Portuguese descent that displayed a pattern of dominantly inherited ALS/motor neuron disease across four generations (4). Subsequent studies identified the mutation in at least seven different families, all of Portuguese-Brazilian origin, each displaying a different clinical course ranging from late-onset spinal muscular atrophy (SMA) to typical and atypical ALS (4). Our previous work identified only a single case of a VAPB mutation (P56S) in a screen of 80 familial ALS samples, demonstrating that VAPB mutations are extremely rare (5). As such, why is it important...
Read more
View all comments by John Landers
|
|
|
|
|
Related News: ER Struggles in Motor Neurons That Fall to ALS
Comment by: Manuel Portero
|
|
|
Submitted 1 April 2009
|
Posted 1 April 2009
|
|
|
This paper from Saxena et al. is a very interesting, even outstanding paper. Despite that ER stress has been conceptually linked before to ALS development, the experiments performed here offer a novel view on the chronology of facts before denervation and symptom development in relevant experimental models. It should be useful also for other diseases, where ER stress has been also involved.
Several findings are really surprising: 1) the clear division between resistant motor neurons (RES) and vulnerable ones (VUL); 2) the predictability on development of the disease that the pathogenic scheme described by authors allows; 3) the dissociation between ubiquitination—often considered a pathological hallmark for this disease and other neurodegenerative diseases—and real axonal pathology; 4) the very early changes at a cellular level (as early as postnatal 5 in some markers) that preclude pathological changes; 5) the presence of novel markers of the disease at an immunological level (such as ATF3, PERK, and similar); 6) the distinctive patterns of expression between RES...
Read more
View all comments by Manuel Portero
|
|
|
|
|
Related News: ER Struggles in Motor Neurons That Fall to ALS
Comment by: P.F. Jennings
|
|
|
Submitted 8 April 2009
|
Posted 9 April 2009
|
|
|
This paper from Eckhart Mandelkow's group seems directly related to the question at hand:
Ebneth A, Godemann R, Stamer K, Illenberger S, Trinczek B, Mandelkow E.
Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer's disease. J Cell Biol. 1998 Nov 2;143(3):777-94. Abstract
View all comments by P.F. Jennings
|
|
|
|
| |
Submit a Comment on this News Article |
|
|
|
|
|
Home
