Researchers find a cause of Parkinson's disease October 2, 2023

[keepontruckin]

https://www.sciencedaily.com/releases/2023/10/231002124357.htm

"A significant breakthrough sheds light on the underlying mechanisms of Parkinson's disease, offering the potential for innovative treatments in the future...

For the first time, we can show that mitochondria, the vital energy producers within brain cells, particularly neurons, undergo damage, leading to disruptions in mitochondrial DNA[LP1] . This initiates and spreads the disease like a wildfire through the brain, ...

By examining both human and mouse brains, researchers discovered that the damage to mitochondria in brain cells occurs and spreads when these cells have defects in anti-viral response genes...

Small fragments of -- actually DNA -- from the mitochondria are released into the cell. When these fragments of damaged DNA are misplaced, they become toxic to the cell, prompting nerve cells to expel this toxic mitochondrial DNA, ...

She also expressed hope that "detecting the damaged mitochondrial DNA could serve as an early biomarker for disease development."...

Professor Issazadeh-Navikas also envisions the possibility of detection of damaged mitochondrial DNA in the bloodstream, making it feasible to diagnose the disease or gauge treatment responses through a simple blood test.

The researchers' next endeavor involves investigating how mitochondrial DNA damage can serve as predictive markers for different disease stages and progression. "Furthermore, we are dedicated to exploring potential therapeutic strategies aimed at restoring normal mitochondrial function to rectify the mitochondrial dysfunctions implicated in the disease."

 

[Wishful]

This sounds potentially useful for ME research too: a new mechanism linking viral response to cell functionality, in a way that can spread. Maybe, for example, there's a similar response in astrocytes, which affects how their connections to neurons work, and instead of spreading evenly, it spreads differently for each individual, resulting in ME's myriad of symptoms. Hopefully some researchers will read this study and get a new perspective on ME. Sadly, others will hold to their old dogma.

 

[Nord Wolf]

I'm not sure how significant a breakthrough it actually is. This article written in 2009 states basically the same things, though not specific to PD, but rather all neurodegenerative diseases.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680182/

My wife has PD and studies all the time, much like we do on M.E. Anytime she finds an article claiming a new breakthrough, she finds another article citing the same things that was published years ago.

Of course, we really do wish that science is actually closer to a cure like they state, but we hear that all the time with other dysautonomia conditions like PoTS, M.E., etc, unfortunately.

 

[datadragon]

It has been well-established that people who carry mutations in both copies of either PINK1 or Parkin develop Parkinson's disease because of ineffective mitophagy. Imagine two workers in a neuronal recycling plant. It's their job to recycle mitochondria, the energy producers of the cell, that are too old or overworked. If the dysfunctional mitochondria remain in the cell, they can cause cellular dysfunction. The process of recycling or removing these old mitochondria is called mitophagy. The two workers in this recycling process are the genes Parkin and PINK1. In a normal situation, PINK1 activates Parkin to move the old mitochondria into the path to be recycled or disposed of. Parkin has another important job that had previously been unknown. The gene also functions in a different path way in the synaptic terminal -- unrelated to its recycling work -- where it controls dopamine release. We showed that dopaminergic synapses become dysfunctional before neuronal death occurs. https://www.sciencedaily.com/releases/2023/09/230915163328.htm

α-Synuclein misfolding and aggregation plays a major role in the pathogenesis of Parkinson's disease. Although loss of function mutations in the ubiquitin ligase, parkin, cause autosomal recessive Parkinson's disease, there is evidence that parkin is inactivated in sporadic Parkinson's disease. Whether parkin inactivation is a driver of neurodegeneration in sporadic Parkinson's disease or a mere spectator is unknown. Here we show that parkin in inactivated through c-Abelson kinase phosphorylation of parkin in three α-synuclein-induced models of neurodegeneration. This results in the accumulation of parkin interacting substrate protein (zinc finger protein 746) and aminoacyl tRNA synthetase complex interacting multifunctional protein 2 with increased parkin interacting substrate protein levels playing a critical role in α-synuclein-induced neurodegeneration, since knockout of parkin interacting substrate protein attenuates the degenerative process. Thus, accumulation of parkin interacting substrate protein links parkin inactivation and α-synuclein in a common pathogenic neurodegenerative pathway relevant to both sporadic and familial forms Parkinson's disease. Thus, suppression of parkin interacting substrate protein could be a potential therapeutic strategy to halt the progression of Parkinson's disease and related α-synucleinopathies. https://pubmed.ncbi.nlm.nih.gov/31237944/

zinc may have an unexpected role in preventing the accumulation of alpha-synuclein by enhancing a transport protein called albumin to inhibit clustering. https://www.medicalnewstoday.com/articles/parkinsons-disease-prevention-zinc-alpha-synuclein In Parkinson's, a protein called alpha-synuclein becomes misfolded, accumulates inside neurons, and slowly poisons the cells. zinc is an essential micronutrient for human metabolism that facilitates protein folding, and helps regulate gene expression,

Parkinson's disease can begin in the gut and spread to the brain via the vagus nerve https://www.sciencedaily.com/releases/2019/06/190626125102.htm The gene Shank3 regulates intestinal barrier function (the gut barrier), and also involved with zinc uptake in the gut. The protein encoded by the SHANK3 gene also turns out is regulated by zinc. NLRP3 overactivation lowers Shank3 levels.

In this investigation, we addressed the possibility that circulating RBC-EVs might contribute to the development of α-Synuclein pathology in the gut by determining that RBC-EVs can be taken up by the gut and transferred to the enteric nerves. Moreover, the uptake of RBC-EVs depends on the local permeability of the gut-vascular barrier (GVB), which varies between regions, and can be influenced by molecules produced by the gut microbiome. https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.29620 Zinc and butyrate help with the gut barrier dysbiosis.

Gene therapy is one way they may be able to target it also. All PD patients show a loss of dopaminergic neurons in the brain and increased levels of a protein called α-synuclein, which accumulates in Lewy bodies. Lewy bodies are a pathological feature of both familial and sporadic forms of the disease, as well as some types of dementia. Therefore, we looked at ways to prevent the expression of α-synuclein and effectively eliminate the physiological cause of PD. To do this, the researchers designed short fragments of DNA that are mirror images of sections of the α-synuclein gene product. The constructs were stabilized by the addition of amido-bridging. The resulting fragments, called amido-bridged nucleic acid-modified antisense oligonucleotides (ASOs), bind to their matching mRNA sequence, preventing it from being translated into protein. After screening 50 different ASOs, the researchers settled on a 15-nucleotide sequence that decreased α-synuclein mRNA levels by 81%. When we tested the ASO in a mouse model of PD, we found that it was delivered to the brain without the need for chemical carriers," says co-lead author Chi-Jing Choong. "Further testing showed that the ASO effectively decreased α-synuclein production in the mice and significantly reduced the severity of disease symptoms within 27 days of administration. Explains senior author of the study Hideki Mochizuki, "Our results showed that gene therapy using α-synuclein-targeting ASOs is a promising strategy for the control and prevention of PD. We expect that in the future, this method will be used to not only successfully treat PD, but also dementia caused by α-synuclein accumulation." https://www.sciencedaily.com/releases/2019/06/190607110520.htm

Another gene therapy approach: Inhibiting or deleting just a single gene, the gene that encodes PTB, transforms several types of mouse cells directly into neurons. More recently, Fu and Hao Qian, PhD, another postdoctoral researcher in his lab, took the finding a big step forward, applying it in what could one day be a new therapeutic approach for Parkinson's disease and other neurodegenerative diseases. Just a single treatment to inhibit PTB in mice converted native astrocytes, star-shaped support cells of the brain, into neurons that produce the neurotransmitter dopamine. As a result, the mice's Parkinson's disease symptoms disappeared. https://www.sciencedaily.com/releases/2020/06/200625102540.htm

 

[Violeta]

It has been well-established that people who carry mutations in both copies of either PINK1 or Parkin develop Parkinson's disease because of ineffective mitophagy. Imagine two workers in a neuronal recycling plant. It's their job to recycle mitochondria, the energy producers of the cell, that are too old or overworked. If the dysfunctional mitochondria remain in the cell, they can cause cellular dysfunction. The process of recycling or removing these old mitochondria is called mitophagy. The two workers in this recycling process are the genes Parkin and PINK1. In a normal situation, PINK1 activates Parkin to move the old mitochondria into the path to be recycled or disposed of. Parkin has another important job that had previously been unknown. The gene also functions in a different path way in the synaptic terminal -- unrelated to its recycling work -- where it controls dopamine release. We showed that dopaminergic synapses become dysfunctional before neuronal death occurs. https://www.sciencedaily.com/releases/2023/09/230915163328.htm

Dietary vitamin B5 derivatives effectively rescue CoA/acetyl-CoA levels and mitochondrial function, reversing the PINK1 deficiency phenotype.

Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism​

https://pubmed.ncbi.nlm.nih.gov/35504872/

 

[datadragon]

Dietary vitamin B5 derivatives effectively rescue CoA/acetyl-CoA levels and mitochondrial function, reversing the PINK1 deficiency phenotype.

Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism​

Yes. A very big finding was that about 50 human genetic diseases due to defective enzymes can be remedied or ameliorated by the administration of high doses of the vitamin component of the corresponding coenzyme, which at least partially restores enzymatic activity. https://www.sciencedirect.com/science/article/pii/S0002916523061701?via=ihub

In other words, taking a high dose of a vitamin can restore a poor genetic gene function in some cases. And some examples would be using riboflavin (b2), as the primary defect in the 677C→T mutated MTHFR enzyme is altered FAD binding. https://pubmed.ncbi.nlm.nih.gov/12560354/ Riboflavin (vitamin B(2)) is the precursor for FAD, the cofactor for methylenetetrahydrofolate reductase (MTHFR) and taking high dose helps to restore function. https://pubmed.ncbi.nlm.nih.gov/12560354/

And another I recently found was for wilsons disease and ceruloplasmin. Ceruloplasmin secretion-based drug screening identified all-trans retinoic acid (ATRA) and other active Vitamin A metabolites as promising candidates for rescuing Ceruloplasmin secretion. ATRA also alleviated reactive oxygen species (ROS) production induced by lipid accumulation in Wilsons Disease-specific hepatocytes. In wilsons disease some people have genetics that cause this although I found it can happen just from excessive chronic inflammation. https://www.biorxiv.org/content/10.1101/2021.08.10.455792v1

However I also am finding that some of the genetics that are changed like MTHFR exist due to balancing of inflammation levels, where certain groups among the population such as blood type A are looking to be normal to have these mutations due to how they balance inflammation differently and should not by itself assume its bad and to fix it. So alongside new research into gene therapy and drug development, learning about the natural function of the nutrients and enzymes can also be quite helpful.