Researchers in the UK and Canada have found the protein Rab32 appears in large quantities in autopsied brain tissue of those who had MS. Higher levels of this protein cause a disruption of communication between cells, and lead to mitochondrial malfunction and neurodegeneration. Researchers say they do not know what causes this increase in Rab32, but they believe that by inhibiting this protein with new treatments, they can slow MS progression. However, neurovascular researchers have been studying this mechanism for many years in Alzheimer's, ALS, Parkinson's and dementia---and vascular researchers know why this happens (keep reading.)
I find it's always a good idea to read the actual research, rather than rely on click bait or fake news headlines. Many medical reporters have only a basic understanding of science. The researchers who send out press releases like to keep it that way. The news stories continue to mention the autoimmune theory of MS right at the start, yet this new discovery has little to do with autoimmune disease, and almost everything to do with inflammation of the vasculature and endothelial dysfunction.
Here is the complete paper:
Together, using multiple patient tissue samples, our findings indicate that Rab32 increases dramatically in neurons and macrophages/microglia localized within active MS lesions and that high amounts of Rab32 coincide with the expression of CHOP. In contrast, chronic MS lesions show Rab32 predominantly in neurons.
“Rab32 is just one of the proteins that is having the effect of drawing the ER and mitochondria too close. There are dozens of other possibilities,” he said.
So, as we learn when digging a bit deeper into the research, it's not just about the increase of Rab32. This just makes a great headline, and will fund ongoing research for these labs. But there are other unfolded proteins causing cellular disruption.
At the center of this "discovery" is the endoplasmic reticulum (ER) and ER stress. The ER is a membraneous structure of a cell, it connects to the nucleus and provides a protective and cleansing function. Red blood cells do not have ERs...but the liver or pancreas cells have lots of them. So does the brain. This is because the ER allows for protein synthesis. And we've known about ER stress in other disease for quite a while. So, to catagorize this as a "discovery" is not really true. It's just new for MS researchers to look at how ER stress is linked in Rab32 increases in the MS brain.
The link of ER stress and neurodegeneration is not new.
The ER stress-associated cell death pathways have been recognized in the numerous pathophysiological conditions, such as diabetes, hypoxia, ischemia/reperfusion injury, and neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and bipolar disorder.
Under various pathological conditions, the perturbation of any of the three physiological functions of the ER results in so-called ER stress and can lead to an accumulation of the newly synthesized unfolded and misfolded proteins in the ER. Among the stimuli that promote ER stress are ischemia, inflammation, and disorders that impair the ER’s ability to properly fold polypeptides or eliminate unfolded proteins (11).
Thanks to the work of vascular researchers, we know a few things which can create ER stress. I suggest reading this complete paper. link
But to summarize:
ER Stress, Endothelial Dysfunction and unfolded protein response are caused by:
1. High levels of homocysteine
2. Disturbed blood flow and lack of good shear stress
3. High levels of bad cholesterol (LDL) and low levels of good cholesterol (HDL)
4. High levels of glucose
5. High blood pressure and obesity
All the stuff mentioned in the Endothelial Health Program.
There are things you can do today to improve health and reduce ER stress.
A final thought for blog readers---targeting one misfolded or rogue protein without considering the mechanism which leads to this perturbation may not be the most successful approach. This is my main concern, and why I wrote this post. We have learned this through years of Alzheimer's research and treatment targeting the beta amyloid protein, which still has no success in alleviating the disease process. In contrast, a multimodal lifestyle approach employed at UCLA led to Alzheimer's disease reversal. link
Big picture: why do cerebral hypoperfusion, cerebral endothelial cell aptosis, a breakdown of the blood brain barrier, ER stress and neurodegeneration occur?
Continue to dig deeper, past the MS News headlines.
There is truth beneath all of the hyperbole.
I am happy to answer some of your questions. While these news articles have not reported our findings appropriately, the discovery that we had described goes beyond the description that ER stress is found in MS brains. Rab32 is a protein that causes mitochondrial dysfunction, as well as mitophagy. It therefore connects ER stress to mitochondrial problems, which could then cause activation of the immune system. Feel free to contact me, it's always a good idea to ask at the source! Thomas.Simmen@ualberta.ca
Thank you for this response, Thomas. But I actually don't have any questions for you. I can read, and understand the mitochondrial dysfunction activated by Rab32. You and your fellow researchers have stated plainly that Rab32 is one of many potential misfolded proteins implicated in ER stress. The program I have created- with the help of Stanford endothelial researchers- addresses the big picture and is available today, for free. My husband is 10 years past an MS diagnosis, with a reversal of gray matter atrophy, remyelination of lesions, and a return to conducting, composing full time and traveling the globe. Using objective science (MRI, blood tests, cerebral perfusion measurements, physical assessment) we can see that he has reversed the MS disease process. Google "Jeff Beal" to follow his career and story. Here is the life-style program we put together for him http://ccsvi.org/index.php/helping-myself/endothelial-health It's always a good idea to ask the source. JoanDelete
And for the blog readers interested in learning more, I always give links to the complete publications in my blog postings--Delete
A final thought for blog readers---targeting one misfolded or rogue protein without considering the mechanism which leads to this perturbation may not be the most successful approach. This is my main concern, and why I wrote this post. We have learned this through years of Alzheimer's research and treatment targeting the beta amyloid protein, which still has no success in alleviating the disease process. In contrast, a multimodal lifestyle approach employed at UCLA led to Alzheimer's disease reversal. https://www.sciencedaily.com/releases/2016/06/160616071933.htm Big picture: why do cerebral hypoperfusion, cerebral endothelial cell aptosis, a breakdown of the blood brain barrier, ER stress and neurodegeneration occur?ReplyDelete