Potential cause found - another RAB32 link

[Luvsadonut]

Breakthrough in multiple sclerosis research as scientists discover possible cause of the disease

http://trib.al/NaAauSM

Scientists have long suspected that mitochondria, the energy-creating "powerhouse" of the cell, plays a link in causing multiple sclerosis.

Using human brain tissue samples, researchers at the Universities of Exeter and Alberta found a protein called Rab32 is present in large quantities in the brains of people with MS - but is virtually absent in healthy brain cells.

Where Rab32 is present, the team discovered that a part of the cell which stores calcium gets too close to the mitochondria.

The resulting miscommunication with the calcium supply triggers the mitochondria to misbehave, ultimately causing toxicity for brain cells in people with MS.

Researchers do not yet know what causes an unwelcome influx of Rab32 but they believe the defect could originate at the base of the cell.

[NHE]

Rab32 connects ER stress to mitochondrial defects in multiple sclerosis.
J Neuroinflammation. 2017 Jan 23;14(1):19.

• BACKGROUND: Endoplasmic reticulum (ER) stress is a hallmark of neurodegenerative diseases such as multiple sclerosis (MS). However, this physiological mechanism has multiple manifestations that range from impaired clearance of unfolded proteins to altered mitochondrial dynamics and apoptosis. While connections between the triggering of the unfolded protein response (UPR) and downstream mitochondrial dysfunction are poorly understood, the membranous contacts between the ER and mitochondria, called the mitochondria-associated membrane (MAM), could provide a functional link between these two mechanisms. Therefore, we investigated whether the guanosine triphosphatase (GTPase) Rab32, a known regulator of the MAM, mitochondrial dynamics, and apoptosis, could be associated with ER stress as well as mitochondrial dysfunction.
  
  METHODS: We assessed Rab32 expression in MS patient and experimental autoimmune encephalomyelitis (EAE) tissue, via observation of mitochondria in primary neurons and via monitoring of survival of neuronal cells upon increased Rab32 expression.
  
  RESULTS: We found that the induction of Rab32 and other MAM proteins correlates with ER stress proteins in MS brain, as well as in EAE, and occurs in multiple central nervous system (CNS) cell types. We identify Rab32, known to increase in response to acute brain inflammation, as a novel unfolded protein response (UPR) target. High Rab32 expression shortens neurite length, alters mitochondria morphology, and accelerates apoptosis/necroptosis of human primary neurons and cell lines.
  
  CONCLUSIONS: ER stress is strongly associated with Rab32 upregulation in the progression of MS, leading to mitochondrial dysfunction and neuronal death.

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[ElliotB]

Come on now, everyone knows MS is caused by CCSVI and lack of sunlight!

[Luvsadonut]

Is it not possible that this could cause CCSVI which in turn creates MS symptoms for some people?

[cheerleader]

Why, Elliot!

Your sarcastic comment is right on point!
Elevated levels of Rab32 and endoplasmic reticular (ER) stress have been found related to disrupted blood flow and endothelial dysfunction. Already published by vascular researchers. Contributors to ER stress include low levels of NO (potentially from lack of UV rays), oxidative stress, high levels of bad cholestrol, high ingestion of sugar, lack of shear stress from inactivity. You know, all that stupid lifestyle stuff I put in the Endothelial Health Program. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181710/

ER stress and elevated, misfolded proteins are not unique to MS, but found in Alzheimer's, dementia and ischemic injury--other neurovascular diseases of neurodegeneration.
http://www.sciencedirect.com/science/ar ... 3112001273

And it's not just Rab32...the MS researchers admit there could be other misfolded proteins, as well.
They also note that Rab32 is likely not the only important protein when it comes to unraveling the mystery of MS.
“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.
http://www.mdmag.com/medical-news/cell- ... n-ms-study

Poston et al. (147) identified several proteins related to different neuronal-based diseases, such as movement disorders (chorea and Parkinson’s disease), genetic disorders (Huntington’s disease), and neurodegenerative diseases (schizophrenia, dementia, and seizures). This evidence suggests that several neuronal disorders share an alteration of MAMs homeostasis, where two crucial organelles (the mitochondrion and the ER) for neuronal cells are in close contact with a
sustained cross-talk. We can therefore speculate that neuronal diseases are MAMs-related disorders.
http://mcms.unife.it/it/ricerca-1/ambit ... ns/167.pdf

But, whatever. Make fun of the vascular research. Pile on!
We're laughing (and jogging/traveling the globe/feeling terrific) every single day.

Here's more on the research, with links to published papers--
http://ccsviinms.blogspot.dk/2017/04/th ... 2-and.html

Joan

[Scott1]

Hi,

This is a good article on the subject.

http://multiple-sclerosis-research.blog ... se-of.html

Regards,

[1eye]

http://www.thisisms.com/forum/chronic-c ... ml#p247336

Readers of this and other recent books and articles may be coming to the realization that MS, "chronic fatigue syndrome" and a number of other diseases previously thought of as somehow "auto-immune" (whatever that is), are really a spectrum of disorders of the blood circulation, and more specifically, the circulation of food and oxygen to mitochondria. These critical parts of each cell nucleus are supposed to help the muscles (blood vessels have more muscle tissue than any other part of the body) burn carbohydrate and oxygen. They do this with the help of a chemical called ATP. But the mitochondria of these sick people, for various reasons, cannot do their job properly. The result in extreme cases is overall weakness which can make it impossible to get up off the floor, or bed.

The operation of smooth muscle tissue, used to expand and contract blood vessels, may be the energy budget item which is missing in these spectrum disorders of mitochondria. In MS the temperature is very sensitive, which leads to the conclusion that the reaction which is broken in these mitochondria is likely more critically broken by elevated temperatures. At these higher temperatures the weakness of smooth muscle cells compounds, because the body's cooling system is broken, further speeding up the broken reactions in the mitochondrial energy system, and making cooling even more difficult.

Remember our thermometers for body temperature are accurate to three digits, meaning the body's temperature control, by changing vessel diameters, has to be a tightly controlled system. The smooth muscles of blood vessels change blood flow as the 4th power of the vessel's diameter.

Medical science has neglected the venous part of this circulation, but the veins and venous circulation may be where the mitochondrial function is being broken.

[ruggierifp]

Google translator

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[Leonard]

CONCLUSIONS: ER stress is strongly associated with Rab32 upregulation in the progression of MS, leading to mitochondrial dysfunction and neuronal death.[/list]

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of course, mitochondria fail successively and are filled with calcium.

see http://www.thisisms.com/forum/general-d ... ml#p245692 to understand the underlying processes...