How protein clumps damage cells in Parkinson’s

Biologists studying Parkinson’s disease have long hoped to solve the mystery of the telltale “clumps.” Scientists want to know how clumps of misfolded proteins damage brain cells and contribute to the disease.

Corinne Lasmézas, PhD, and her Scripps Research colleagues have now cracked the case of pα-syn*, a protein clump that is particularly toxic to the cells. Their recent study in the journal Neurobiology of Disease shows that pα-syn* causes damage by recruiting certain enzymes and an accomplice to damage cells. The accomplice is a protein called tau.

“We really felt like detectives in this study,” says Lasmézas, a professor on the Florida campus of Scripps Research. “We hope that this research into the root cause of Parkinson’s will bring us closer to finding a disease-modifying treatment.”

Parkinson’s disease is the most common neurodegenerative disease after Alzheimer’s. The disease strikes when the brain starts losing the cells that produce dopamine, a critical neurotransmitter.

Parkinson’s can have many causes, from genetics to environmental factors, but a protein called α-synuclein (α-syn in short) is found to turn bad and form clumps in every case. The Lasmézas lab has discovered that a particular type of α-syn clumps, or “aggregates,” that they called pα-syn*, starts to show up around cellular structures called mitochondria. This is a big problem for cells, which need mitochondria to produce their energy.

“We can see the mitochondria break into fragments in these cells,” says Lasmézas. “We wanted to understand the mechanism behind this.”

The investigation relied on a combination of cultured neurons and a mouse model of Parkinson’s, as well as analysis of donated brain tissues from deceased Parkinson’s disease patients.

The new research shows that pα-syn* hurts mitochondria by starting a cascade of events. First, pα-syn* activates a pathway in cells called the MAPK pathway. Enzymes of the MAPK pathway then modify the protein tau. This was a fascinating finding, since tau has long puzzled neuroscientists. Tau is known to form tangles inside neurons in the brains of Parkinson’s disease patients. But scientists did not know how they got there or what they were doing.

Lasmézas and her team found that enzymes of the MAPK pathway modify tau through a process called phosphorylation. This version of tau then clumps together with pα-syn* on the mitochondrial membrane. The two protein aggregates grow bigger and bigger, destroying the mitochondria in the process.

At last, the researchers knew what pα-syn* was doing and how it hurt cells. “We’ve shown how pα-syn* works as the main trigger in mitotoxicity,” says Lasmézas.

Study first author Diego Grassi, PhD, a research associate at Scripps Research at the time of the study, stresses the importance of discovering tau’s role in destroying mitochondria. Scientists know tau is involved in Alzheimer’s disease, so this study suggests a mechanism behind how Alzheimer’s and Parkinson’s overlap at the molecular level. The presence of α-syn and tau aggregates is also a telltale sign of other forms of dementia, and now scientists know how this might occur.

“This is also important for its possible implications in other neurodegenerative disorders,” says Grassi.

Lasmézas and Grassi say the next step in this research is to study how to stop pα-syn*, with the ultimate goal of treating Parkinson’s disease.

“I know we are doing something that could make a meaningful difference in the quality of life of people affected by this condition,” says Grassi. “I can hardly imagine a place better than Scripps Research to perform this kind of translational activity.”

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Story Source:

Materials provided by Scripps Research Institute. Note: Content may be edited for style and length.

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Journal Reference:

1. Diego Grassi, Natalia Diaz-Perez, Laura A. Volpicelli-Daley, Corinne Ida Lasmézas. Pα-syn* mitotoxicity is linked to MAPK activation and involves tau phosphorylation and aggregation at the mitochondria. Neurobiology of Disease, 2019; 124: 248 DOI: 10.1016/j.nbd.2018.11.015

https://www.sciencedaily.com/releases/2018/12/181220141130.htm

Human blood cells can be directly reprogrammed into neural stem cells

Scientists from the German Cancer Research Center (DKFZ) and the stem cell institute HI-STEM* in Heidelberg have succeeded for the first time in directly reprogramming human blood cells into a previously unknown type of neural stem cell. These induced stem cells are similar to those that occur during the early embryonic development of the central nervous system. They can be modified and multiplied indefinitely in the culture dish and can represent an important basis for the development of regenerative therapies.

Stem cells are considered to be the all-rounders of our tissues: they can multiply indefinitely and then — if they are pluripotent embryonic stem cells — generate all conceivable cell types. In 2006, the Japanese scientist Shinya Yamanaka recognized that such cells could also be produced in the laboratory — from mature body cells. Four genetic factors alone are sufficient to reverse the course of development and produce so-called induced pluripotent stem cells (iPS) that have identical properties to embryonic stem cells. Yamanaka was awarded the Nobel Prize for Medicine in 2012 for this discovery.

“This was a major breakthrough for stem cell research,” said Andreas Trumpp, German Cancer Research Center (DKFZ) and Director of HI-STEM in Heidelberg. “This applies in particular to for research in Germany, where the generation of human embryonic stem cells is not permitted. Stem cells have enormous potential both for basic research and for the development of regenerative therapies that aim to restore diseased tissue in patients. However, reprogramming is also associated with problems: For example, pluripotent cells can form germ line tumors, so-called teratomas.

Another possibility is not to completely turn back the course of development. For the first time, Trumpp’s team has succeeded in reprogramming mature human cells in such a way that a defined type of induced neural stem cells is produced that can multiply almost indefinitely. “We used four genetic factors like Yamanaka, but different ones for our reprogramming,” explains Marc Christian Thier, first author of the study. “We assumed that our factors would allow reprogramming to an early stage of development of the nervous system.”

In the past, other research groups also reprogrammed connective tissue cells into mature nerve cells or neural precursor cells. However, these artificially produced nerve cells often could not be expanded and could therefore hardly be used for therapeutic purposes. “Often, it was a heterogeneous mixture of different cell types that might not exist in the body under physiological conditions,” said Andreas Trumpp explaining the problems.

Together with stem cell researcher Frank Edenhofer from the University of Innsbruck and neuroscientist Hannah Monyer from DKFZ and the Heidelberg University Hospital, Trumpp and his team have succeeded in reprogramming different human cells: connective tissue cells of the skin or pancreas as well as peripheral blood cells. “The origin of the cells had no influence on the properties of the stem cells,” said Thier. In particular, the possibility of extracting neural stem cells from the blood of patients without invasive intervention is a decisive advantage for future therapeutic approaches.

What is special about the reprogrammed cells of the Heidelberg researchers is that they are a homogeneous cell type that resembles a stage of neural stem cells that occurs during the embryonic development of the nervous system. “Corresponding cells exist in mice and probably also in humans during early embryonic brain development,” said Thier. “We have described here a new neural stem cell type in the mammalian embryo.

These so called “induced Neural Plate Border Stem Cells” (iNBSCs) have a broad development potential. The iNBSCs of the Heidelberg scientists are expandable and multipotent and can develop in two different directions. On the one hand, they can take the path of development to mature nerve cells and their supplier cells, the glial cells, i.e. become cells of the central nervous system. On the other hand, they can also develop into cells of the neural crest, from which different cell types emerge, for example peripheral sensitive nerve cells or cartilage and bones of the skull.

The iNBSCs thus form an ideal basis for generating a broad range of different cell types for an individual patient. “These cells have the same genetic material as the donor and are therefore presumably recognized as “self” by the immune system and are not rejected,” explains Thier.

The CRISPR/Cas9 gene scissors can be used to modify the iNBSC or repair genetic defects, as the scientists have shown in their experiments. “They are therefore of interesting both for basic research and the search for new active substances and for the development of regenerative therapies, for example in patients with diseases of the nervous system. However until we can use them in patients, a lot of research work will still be necessary,” emphasizes Trumpp.

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Story Source:

Materials provided by German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). Note: Content may be edited for style and length.

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Journal Reference:

1. Marc Christian Thier, Oliver Hommerding, Jasper Panten, Roberta Pinna, Diego García-González, Thomas Berger, Philipp Wörsdörfer, Yassen Assenov, Roberta Scognamiglio, Adriana Przybylla, Paul Kaschutnig, Lisa Becker, Michael D. Milsom, Anna Jauch, Jochen Utikal, Carl Herrmann, Hannah Monyer, Frank Edenhofer, Andreas Trumpp. Identification of Embryonic Neural Plate Border Stem Cells and Their Generation by Direct Reprogramming from Adult Human Blood Cells. Cell Stem Cell, 2018; DOI: 10.1016/j.stem.2018.11.015

https://www.sciencedaily.com/releases/2018/12/181221123721.htm

Top Trump official calls U.S. bank CEOs amid financial market rout

U.S. President Donald Trump‘s Treasury secretary called America’s top bankers on Sunday and said he got reassurances about the health of the nation’s banks amid an ongoing rout on Wall Street.

U.S. stocks have plunged in recent weeks on concerns over slowing economic growth, with the S&P 500 index <.SPX> on pace for its biggest percentage decline in December since the Great Depression.

“Today I convened individual calls with the CEOs of the nation’s six largest banks,” Treasury Secretary Steven Mnuchin said on Twitter shortly before financial markets were due to open in Asia.

The Treasury said in a statement that Mnuchin talked with the chief executives of Bank of America(NYSE: BAC), Citi (NYSE: C), Goldman Sachs (NYSE: GS), JP Morgan Chase (NYSE: JPM), Morgan Stanley (NYSE: MS) and Wells Fargo (NYSE: WFC).

“The CEOs confirmed that they have ample liquidity available for lending,” the Treasury said.

Mnuchin “also confirmed that they have not experienced any clearance or margin issues and that the markets continue to function properly,” the Treasury said.

Mnuchin’s calls to the bankers came amid a partial government shutdown that began on Saturday following an impasse in Congress over Trump’s demand for more funds for a wall on the border with Mexico. Financing for about a quarter of federal government programs expired at midnight on Friday and the shutdown could continue to Jan 3.

The Treasury said Mnuchin will convene a call on Monday with the president’s Working Group on Financial Markets, which includes Washington’s main stewards of the U.S. financial system and has been known colloquially as the “Plunge Protection Team.”

The group, which was also convened in 2009 during the latter stage of the financial crisis, includes officials from the Federal Reserve as well as the Securities and Exchange Commission.

Wall Street is also closely following reports that Trump has privately discussed the possibility of firing Federal Reserve Chairman Jerome Powell. Mnuchin said on Saturday Trump told him he had “never suggested firing” Powell.

Trump has criticized the U.S. central bank for raising interest rates this year, which could further dampen economic growth. The Fed’s independence is seen as a pillar of the U.S. financial system.

Mnuchin’s calls come as a range of asset classes have suffered steep losses.

In December alone, the S&P 500 <.SPX> is down nearly 12.5 percent, while the Nasdaq Composite <.IXIC> has slumped 13.6 percent. The Nasdaq is now in a bear market, having declined nearly 22 percent from its record high in late August, and the S&P is not far off that level.

Corporate credit markets have been under duress as well, and measures of the investment grade corporate bond market are poised for their worst yearly performance since the 2008 financial crisis.

The high-yield bond market, where companies with the weakest credit profiles raise capital, has not seen a deal all month. The last time that happened was in November 2008.

https://www.streetinsider.com/Reuters/Treasury+Secretary+convenes+calls+with+top+U.S.+bankers/14950811.html

Cannabis Stocks on Watch: FDA Explores Product Interstate Commerce ‘Pathways’

https://www.streetinsider.com/FDA/Cannabis+Stocks+on+Watch+as+FDA+to+Explore+Pathways+for+Interstate+Commerce+of+Cannabis+Products/14945487.html

Biotech billionaire Mikitani on quest to build pharma firm, closes round at $284M

The latest billionaire to be drawn into the biotech game is doubling down on his California startup with plans to vault it into position as a new-wave pharma company.

Hiroshi “Mickey” Mikitani has contributed to an add-on $134 million tranche for the C round backing Rakuten Aspyrian. That brings the round to $284 million, much of which came directly from the fabulously wealthy Japanese e-tailer.

The Tokyo-based SBI Group — a financial services group with a new-found interest in biotech — also came in on the extra financing. The biotech has raised a total of $372 million in three years.
Mikitani recently took the top job at the company for himself as Aspyrian pushes an EGFR-targeting therapy for head and neck squamous cell carcinomas through Phase III. New mid-stage studies are also being set up for other cancers with an EGFR target, which is quite common.

The Japanese billionaire is backing a new technology that was developed at the National Cancer Institute in the lab of Hisataka Kobayashi, an imaging expert who made a somewhat serendipitous discovery that conjugating an antibody with a dye called IRDye700DX (IR700), infusing it into patients and then hitting it with a near infrared light would cremate cancer cells without off-target toxicity. Kobayashi out-licensed it to Aspyrian Therapeutics, which now goes by the name of Rakuten Aspyrian.

Mikitani became familiar with the work at the NCI as he was hunting down a better therapy for his father, who was dying of pancreatic cancer. And while it was too late to save his father, he seized on it as the next big thing in cancer, backing Aspyrian from the beginning.

https://endpts.com/biotech-billionaire-hiroshi-mickey-mikitani-doubles-down-on-quest-to-build-a-pharma-company-closing-round-at-284m/

Age, BMI Predict Obstructive Sleep Apnea Treatment Success

Among patients with obstructive sleep apnea, older age and reduced body mass index (BMI) are predictors of upper airway stimulation (UAS) treatment response, according to a study published online Nov. 28 in the European Respiratory Journal.

Clemens Heiser, M.D., from Munich Technical University in Germany, and colleagues sought to identify predictors of UAS therapy response in a multicenter registry of 508 patients who underwent UAS implantation in the United States and Germany between October 2016 and January 2018.

The researchers found that the median apnea/hypopnea index reduced from 34 to seven events/hour⁻¹, while the median Epworth sleepiness scale score reduced from 12 to 7 from baseline to 12 months postimplant. For each one-year increase in age, there was a 4 percent increase in the odds of treatment success in post hoc analyses, while there was 9 percent reduced odds of treatment success for each one-unit increase in BMI. Age persisted as a statistically significant predictor of treatment success in multivariable analyses.

“In this largest international report to date, we have for the first time identified ways to predict who will be successfully treated with this obstructive sleep apnea treatment,” a coauthor said in a statement.

Several authors disclosed financial ties to the medical device industry.

Abstract/Full Text (subscription or payment may be required)

https://www.physiciansbriefing.com/pulmonology-17/age-health-news-7/age-bmi-predict-obstructive-sleep-apnea-treatment-success-740153.html

Endurance Exercise Tied to Anti-Aging at Cellular Level

Endurance exercise has anti-aging effects visible at the cellular level, according to a study published online Nov. 28 in the European Heart Journal.

Christian M. Werner, M.D., from Saarland University in Saarbrücken, Germany, and colleagues randomly assigned 124 healthy, previously inactive individuals to a control condition (no change in lifestyle), aerobic endurance training (AET; continuous running), high-intensive interval training (IT; 4×4 method), or resistance training (RT; circle training on eight devices). Each intervention included three 45-minute training sessions per week. Measurements examined the cellular effects of the different training modalities.

The researchers found that maximum oxygen uptake (VO_2max) increased with all three training modalities. In both endurance exercise groups (AET, IT), telomerase activity in blood mononuclear cells was upregulated twofold to threefold, but this effect was not seen with RT. Further, lymphocyte, granulocyte, and leucocyte telomere length (TL) increased in the endurance-trained groups but not in the RT group. A single bout of endurance training, but not RT, acutely increased telomerase activity in CD14+ and in CD34+ leucocytes, as detected with magnet-activated cell sorting with telomerase repeat-amplification protocol assays.

“Endurance training and IT, but not RT, increased telomerase activity and TL which are important for cellular senescence, regenerative capacity, and thus, healthy aging,” the authors write.

Abstract/Full Text
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https://www.physiciansbriefing.com/cardiology-2/misc-aging-news-10/endurance-exercise-tied-to-anti-aging-at-cellular-level-740034.html