'Calcium channels play a role in neuronal homeostasis and elimination of toxic buildup of proteins'

Remy

Administrator
There is no way that this mechanism is not also somehow implicated in MECFS (in my opinion!).

Autophagy, mitophagy...none of these cleanup processes seem to work properly in our population.

Is this study a big clue as to why?

"Proteins hang around, literally gumming up the works and preventing neurons from doing their job."


Taking out the garbage is a crucial step in housecleaning.

Similarly, autophagy is the body’s first-line of defense against the buildup up of toxic substances, degrading old organelles and proteins to provide new substrates and building blocks. In this way, autophagy prevents the buildup of “garbage” that can result in destruction of neurons and cause neurologic diseases.

A forward genetic screen in Drosophila melanogaster (fruit flies) identified mutant copies, or alleles, of a gene called cacophony associated with defects in autophagy and cellular homeostasis. In a report that appears in PLOS BIOLOGY, Dr. Hugo Bellen and his colleagues at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and Baylor, and Dr. Chao Tong, at the Life Sciences Institute and Innovation Center for Cell Biology, Zhejiang University in Hangzhou, China, find that mutations of human homologs (genes that carry out similar functions) of cacophony and its partner straightjacket (Cacna1a and Cacna2d2 respectively) cause defects in autophagy in neurons.

The human homologues of these genes are associated with severe neurologic diseases such as episodic ataxia 2, familial hemiplegic migraine, absence epilepsy, progressive ataxic and spinocerebellar ataxia 6, but the molecular mechanisms by which mutations in these genes cause these diseases are poorly understood so far.

In both flies and mice, loss of autophagy-related genes leads to progressive neurodegeneration, the researchers wrote. This study found that when cacophony and its related gene straitjacket are mutated, they cause similar degenerative phenotypes in the mutant neurons as autophagy mutants. Proteins hang around, literally gumming up the works and preventing neurons from doing their job.

Voltage-gated calcium channels cannot form properly when cacophony is mutated, preventing fusion of the synaptic vesicle with the plasma membrane and neurotransmitter release.

“We were surprised to find that mutations in this gene also affect fusion of autophagic organelles,” said Upasana Gala, a graduate student in the Program in Developmental Biology at Baylor in Bellen’s laboratory.
The authors show that the voltage gated calcium channels are present on the lysosomes that dispose of proteins. In this study, “we argue that when the acidified lysosome is depolarized by a sodium channel, it results in calcium efflux from lysosomes via the calcium channel encoded by the cacophony gene,” they wrote. The calcium efflux results in higher local calcium concentration than the rest of the cell, promoting the fusion of the lysosome with endosomes.

In summary, the authors wrote, “We present a model in which calcium channels play a role in autophagy by regulating the fusion of autophagic vesicles with lysosomes and hence functions in maintaining neuronal homeostasis.”

Bellen is a Howard Hughes Medical Institute investigator and director of the Program in Developmental Biology at Baylor. Tong is an assistant professor at Zhejiang University in Hangzhou, China.

Others who took part in this work include: Sonal Nagarkar Jaiswal, Alberto di Ronza, Manish Jaiswal, Shinya Yamamoto, Hector Sandoval, Lita Duraine, Marco Sardiello, Roy Sillitoe, and Chao Tong, all of Baylor and the NRI at Texas Children’s Hospital and BCM, Xuejun Tian, Yongping Zhang, Weina Shang, Hengyu Fan and Chao Tong, all of Life Sciences Institute and Innovation Center for Cell Biology, Zhejiang University in Hangzhou, China; Kartik Venkatachalam of the University of Texas School of Medicine at Houston and the Program in Developmental Biology at Baylor.

Funding for this work came from the National Basic Research Program of China (Grant 2012CB966600), the National Natural Science Foundation of China (Grant 31271432), the Specialized Research Fund for the Doctoral Program of Higher Education (Grant 20130101110116), the Howard Hughes Medical Institute, the National Institute of Neurological Disorders and Stroke (Grant R01-NS-089664), and National Institute of General Medicine (Grant RC4-GM-096355).
 

Issie

Well-Known Member
I think so too. Having GastroCrom, which is not only a mast cell stablizer but a mild calcium channel blocker had helped not only my MCAS but POTS too.
Also calcium (along with iron and magnesium) is thought to play a part in issues with Lyme disease - which is being found more and more in people with these issues.
Issie
 
Maybe someone with more knowledge could look at this.

FROM: "domain proteins specialize functionally distinct ER-PM contact sites in human cells" - February 2018.
Besprozvannaya M1, Dickson E2, Li H3, Ginburg KS4, Bers DM4, Auwerx J3, Nunnari J1.
Author information
"Abstract
---- Data from an analysis of cells lacking GRAMD2a suggest that it is an organizer of ER-PM MCSs with pleiotropic functions including calcium homeostasis. Thus, our data demonstrate the existence of multiple ER-PM domains in human cells that are functionally specialized by GRAM-domain containing proteins."


From Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017:
"The top 5 differentially methylated regions based on R2 are shown in Table 5, and corresponded to TSS methylation in GRAMD1A".


I came across this on the "Follow ME in Denmark" website. However, they were asking "Is GRAMD1A involved in the dysregulated sterol and sphingolipid homeostasis in ME patients?" I.e. rather than looking at calcium homeostasis.
 

nanobug

Member
BTW, inhibiting mTOR is probably the easiest way to enhance autophagy. This can be done with rapamycin but the highlight of my day, yesterday, was finding out that (drum roll please!) dichloroacetate also appears to inhibit mTOR. Do a search on Pubmed for "dichloroacetate mTOR" and you'll find at least four papers describing this effect.
 

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