TSRI researchers uncover culprit in Parkinson's brain cell die-off

You'll likely need this, so what is your doctor doing to prevent your Parkinsons risk?

Your Parkinsons risk:

Parkinson’s Disease May Have Link to Stroke

https://www.alphagalileo.org/ViewItem.aspx?ItemId=184225&CultureCode=en

05 March 2018 The Scripps Research Institute

Scientists have discovered a connection between neuronal death and Lewy bodies in Parkinson's disease.

An estimated 10 million people worldwide are living with Parkinson’s disease—an incurable neurodegenerative disorder that leads to an increasing loss of motor control. 

If we could peer into the brains of these patients, we’d see two hallmarks of the disease. First, we’d see a die-off of the brain cells that produce a chemical called dopamine. We’d also see protein clumps called Lewy bodies inside the neurons.

Corinne Lasmézas, DVM, PhD, a professor on the Florida campus of The Scripps Research Institute (TSRI), believes a key to treating Parkinson’s is to study possible links between these two phenomena.

Now her group has discovered a connection between neuronal death and Lewy bodies. The research, published recently in the journal Proceedings of the National Academy of Sciences, offers an explanation for why neurons die off in the first place.

‘This study identifies the missing link between Lewy bodies and the type of damage that’s been observed in neurons affected by Parkinson’s,” says Lasmézas, senior author of the  study. “Parkinson’s is a disorder of the mitochondria, and we discovered how Lewy bodies are releasing a partial break-down product that has a high tropism for the mitochondria and destroys their ability to produce energy.” 

Toxic protein travels to mitochondria to do damage

Lewy bodies were described a century ago, but it was not until 1997 that scientists discovered they were made of clumps of a misfolded protein called α-synuclein. When it’s not misfolded, α-synuclein is believed to carry out functions related to the transmission of signals between neurons. 

Lasmézas’ research focuses on neurological disorders caused by misfolded proteins, such as Alzheimer's, Parkinson’s, prion diseases, frontotemporal dementia and amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease). She uses lab models, including cell cultures and mice, to study these diseases. 

In the current study, Lasmézas and her team looked at cell cultures of neurons that were induced to accumulate fibrils made of misfolded α-synuclein, mimicking Lewy bodies in patients with Parkinson’s. They discovered that when α-synuclein fibrils are broken down, it often creates a smaller protein clump, which they named pα-syn* (pronounced “P-alpha-syn-star”).

“Sometimes the nerve cells can efficiently degrade the α-synuclein fibrils, but if they get overwhelmed, the degradation may be incomplete,” she explains. “And it turns out that the result of that partial degradation, pα-syn*, is toxic.” 

Diego Grassi, PhD, a research associate in Lasmézas’ lab, made this discovery by labeling the pα-syn* with an antibody so he could follow it throughout the cell after it was created. He observed that pα-syn* traveled and attached itself to the mitochondria. Further investigation revealed that once the pα-syn* attached, the mitochondria started to break down. These fragmented mitochondria lose their ability to carry an electrochemical signal and produce energy. 

The researchers followed up with an analysis of mouse and human brain samples. They confirmed the existence of pα-syn* in the dopamine-producing neurons.

“The Lewy bodies are big aggregates and they’re sitting in the cell, but they don’t come into direct contact with the mitochondria in the way pα-syn* does,” Lasmézas explains. “With Diego’s discovery, we’ve made a direct connection between the protein α-synuclein and the downstream effects that are observed when brain cells become damaged in Parkinson’s.”

Lasmézas plans to continue studying the connection between misfolded proteins and the destruction of mitochondria in neurons. “What we found may not be the only mechanism of toxicity, but we know it’s important,” she says. “This paper is about identifying where pα-syn* comes from and what it does to the mitochondria, but there’s obviously, mechanistically, a lot that we still don’t know.”

She says that these findings also have implications for designing treatments for Parkinson’s, noting that some drugs currently under development are focused on getting rid of larger fibrils that make up Lewy bodies.

“It’s important to be aware that when Lewy bodies are broken down, these toxic substances may be created,” Lasmézas says. In addition, she adds, the discovery of pα-syn* as an important component of the disease process points to a new target for creating drugs slowing disease progression. 

First author of the study, “Identification of a highly neurotoxic α-synuclein species inducing mitochondrial damage and mitophagy in Parkinson’s disease,” was Diego Grassi. Other authors were Shannon Howard, Minghai Zhou, Natalia Diaz-Perez, and Philip LoGrasso of The Scripps Research Institute; Nicolai T. Urban, Debbie Guerrero-Given, and Naomi Kamasawa of the Max Planck Florida Institute for Neuroscience; and Laura Volpicelli-Daley of the University of Alabama at Birmingham.

This research was funded by the National Institute of Neurological Disorders and Stroke (grant R01NS085223), the Michael J. Fox Foundation and the Saul and Theresa Esman Foundation.

Attached files

• 
  The new study was led by Corinne Lasmézas, PhD, and Diego Grassi, PhD, of the Florida campus of The Scripps Research Institute.

  ---

• Full bibliographic information"Identification of a highly neurotoxic α-synuclein species inducing mitochondrial damage and mitophagy in Parkinson’s disease," by
  Diego Grassi, Shannon Howard, Minghai Zhou, Natalia Diaz-Perez, Nicolai T. Urban, Debbie Guerrero-Given, Naomi Kamasawa, Laura A. Volpicelli-Daley, Philip LoGrasso and Corinne Ida Lasmézas. Proceedings of the National Academy of Science, Feb. 2018

TSRI Chemists Find Efficient, Scalable Way to Synthesize Potential Brain-Protecting Compound - jiadifenolide

Interesting that I have never heard of this. Has your doctor? Looks like lots of research needed on this. I would expect the ASA, NSA and WSO to start up clinical trials in a year. Hell no, they won't do a damn thing about this news.
http://www.alphagalileo.org/ViewItem.aspx?ItemId=153700&CultureCode=en
Chemists at The Scripps Research Institute (TSRI) have invented the first practical, scalable method for synthesizing jiadifenolide, a plant-derived molecule that may have powerful brain-protecting properties.
Finding a good way to synthesize jiadifenolide has been a goal of chemists around the world since the compound was discovered in 2009. Preliminary studies have hinted that it might be useful in protecting brain cells from neurodegenerative diseases such as Alzheimer’s and perhaps other neurological conditions including stroke and traumatic brain injury. But it is very difficult to obtain useful quantities of jiadifenolide from plants, and the synthesis methods reported in the past few years also have low yields.
“Prior synthetic routes to jiadifenolide yield a few milligrams, suitable mainly for cell-culture experiments, but with our new method someone could make the gram to kilogram quantities needed for tests in animals and humans,” said Ryan A. Shenvi, associate professor at TSRI.
The feat by Shenvi and his team, described in an Advance Online Publication in Nature Chemistry on June 15, 2015, may therefore lead to the development, years from now, of a jiadifenolide-derived drug.
The achievement also demonstrates the increasing power of synthetic chemistry to produce the potentially valuable molecules found in nature on large scale at low cost.
“There are more and more examples these days of syntheses that start with cheap, readily available chemicals and assemble them into complex and valuable molecules on a meaningful scale—much more efficiently than if you tried to isolate the molecules from nature or produce them in genetically engineered organisms,” said Shenvi.
A Tantalizing Target
Jiadifenolide is found in trace quantities in the fruit of the star anise-related shrub Illicium jiadifengpi, which grows in southern China. It and other Illicium plants have long featured in Chinese traditional medicine. Most parts of I. jiadifengpi are poisonous if eaten, but root extracts applied to the skin have been used to treat arthritis.
In 2009, a team of Japanese and Chinese scientists reported isolating tiny quantities of jiadifenolide from I. jiadifengpi. They determined that the compound, unlike many others from the plant, is not toxic, and indeed strongly promotes the growth of axons and dendrites (output and input branches) from rat neurons in a culture dish. Subsequent research has suggested that jiadifenolide works by enhancing the activity of natural brain growth factors, known as neurotrophins.
“Neurotrophin levels are depressed in diseases like Alzheimer’s, so researchers have long sought compounds that behave like neurotrophins or that amplify their activity, especially those that could be taken in a pill,” said Shenvi.
Neurotrophins themselves are large molecules that effectively can’t be used as drugs, because they are rapidly broken down by enzymes in the digestive tract and bloodstream and also don’t cross the blood-brain barrier easily. Jiadifenolide by contrast is a small molecule, and thus has more potential to be developed into an oral drug.
‘A Completely Different Approach’       
Shenvi’s laboratory took up the jiadifenolide synthesis challenge a few years after the first, low-yield method was reported in 2011. “While we worked on this, two other groups reported their own synthetic routes, which pushed us to find a completely different approach,” said Hai-Hua Lu, a research associate in the Shenvi laboratory who was lead author of the new study.
The new, eight-step synthesis involves merging two simple molecules, called butenolides, via a process called the Michael reaction—in fact, a double Michael reaction—to make a compound very close to jiadifenolide itself.
“It’s a chemical reaction that few people (myself included) would have confidently predicted to work,” Shenvi said.
“After we figured out how to do that, though, the rest was much easier, and we found we could obtain more than a gram from one batch,” said Lu.
Now that jiadifenolide can be produced in sufficient quantities, Shenvi is looking for companies that can help with further studies of the compound, including tests in animal models of neurodegenerative diseases.
Shenvi also suspects that the new method can be adapted for the practical synthesis of related trace compounds found in Illicium plants.
He admits, though, that it is not just the therapeutic potential of this plant metabolite that has attracted him and other synthetic chemists.
“The peculiar geometry of jiadofenolide lends it a certain beauty, like a geodesic dome or a mosaic tessellation. It’s the combination of structural beauty, chemical challenge and therapeutic potential that has stimulated so much interest,” he said.
The other author of the paper, “An eight-step gram-scale synthesis of (−)-jiadifenolide,” was National Science Foundation (NSF) pre-doctoral fellow Michael D. Martinez, a second-year graduate student in the Shenvi laboratory. “Many related Illicium sesquiterpenes also demonstrate neurotrophic properties and share a common structural core with (-)-jiadifenolide. Our route to access (-)-jiadifenolide may provide inroads to these related natural products and analogues.”
The research was funded in part by the NSF (DGE-1346837), as well as Amgen, Boehringer Ingelheim, the Baxter Foundation, Bristol-Myers Squibb, Eli Lilly, Novartis and the Sloan Foundation.

TSRI scientists map out protein structure involved in cellular function, nervous system development

How much of this protein structure is needed because we are now redeveloping our nervous system? Does your doctor have ANY clue about this need? 

TSRI scientists map out protein structure involved in cellular function, nervous system development

Scientists from The Scripps Research Institute (TSRI), working closely with researchers at the National Institutes of Health (NIH), have mapped out the structure of an important protein involved in cellular function and nervous system development.
The new structure provides crucial information for understanding how the protein binds to cellular components. It's also the first structure determined of any ligase in the tubulin tyrosine ligase-like (TTLL) family.
Scientists have been especially curious about the role of TTLLs because mutations in these proteins have been linked to a range of neurodegenerative diseases, including retinal dystrophy and the rare Joubert syndrome.
"This protein is highly expressed in the nervous system and has an integral role in neuronal development," said Elizabeth Wilson-Kubalek, senior staff scientist in Professor Ron Milligan's laboratory at TSRI and co-first author of the new paper with Christopher Garnham and Annapurna Vemu of the NIH's National Institute of Neurological Disorders and Stroke (NINDS).
The new research was published online ahead of print by the journal Cell.
More at link.

Source:

http://www.scripps.edu/

Scientists Discover a Key Pathway That Protects Cells Against Death by Stress

What is your doctor doing to protect you against the stress of no stroke protocols for getting to 100% recovery? You're under a lot of stress about recovery so DEMAND this protection against cell death.

Scientists Discover a Key Pathway That Protects Cells Against Death by Stress

When it comes to protecting cells from death brought on by the calamities of environmental stress, the human body is particularly ingenious. From cellular components that suck up misfolded proteins to a vigilant immune system, the ways we protect our cells (and ourselves) are many and mysterious.
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have now uncovered the workings of another cell-protection device, one that may play a major role in a number of age-related diseases, including diabetes and Parkinson’s, Alzheimer’s and Huntington’s diseases.
The study, led by Srinivasa Subramaniam, a TSRI assistant professor, and Solomon H. Snyder, a neuroscience professor at Johns Hopkins University School of Medicine, was published February 5 in the journal Cell Reports.
More or Less Acceleration
The study focuses on a new pathway through which Rheb, a regulator that many believe is active in the brain’s ability to change in response to learning, actually plays two roles, rather than one—stimulating and inhibiting protein synthesis.
The interplay between the two roles may be the key that enables cells to alter protein synthesis and protect the cell in response to varying environmental stresses.
“We found Rheb acts like the gas pedal in a car,” Subramaniam said. “It can either increase translation or decrease it. And because translation is a fundamental process that is affected in a lot of diseases, we now think that Rheb may act like a switch in some disease states—helping to turn them off and on.”
Rheb is known to bind and activate mTOR, a developmentally important gene that integrates signals from multiple pathways and regulates critical cell functions such as protein synthesis. Besides its role as an activator of mTOR, which plays a major role in conditions from diabetes to neurodegenerative disease, the mTOR-independent role of Rheb is less known. The new study defines crucial mTOR-independent effects of Rheb. Results showed that, when stressed, Rheb instead inhibits protein synthesis by amplifying the phosphorylation (adding a phosphate group to a protein to alter its function) of another protein known eIF2a. As a result, cell resources can be conserved rather than squandered when the environment is challenging.
“We don’t really understand the full role of the Rheb-mTOR pathway, but we have uncovered a new fundamental process of Rheb that is independent of mTOR and very intriguing,” said Neelam Shahani, a member of Subramaniam’s lab who was co-first author of the study with Richa Tyagi of Johns Hopkins University School of Medicine. “Rheb can inhibit protein synthesis, and we know that protein misfolding via environmental stress factors is present in a lot of diseases.”
Subramaniam noted that, intriguingly, an earlier study had suggested the Rheb pathway had been implicated in Alzheimer’s disease. “We also want to look at Rheb’s role in other neurodegenerative diseases,” he said.
In addition to Subramaniam, Snyder, Shahani and Tyagi, authors of the study, “Rheb Inhibits Protein Synthesis by Activating the PERK-eIF2α Signaling Cascade,” include Max Ferretti, William Pryor, Supriya Swarnkar and Katrin Karbstein of TSRI; Lindsay Gorgen of Florida Atlantic University; as well as Paul F. Worley and Po Yu Chen of Johns Hopkins University School of Medicine.
This work was supported by the State of Florida, the O'Keeffe Neuroscience Scholar Award and the United States Public Health Service (DA000266).