A new clue to the cause of ALS and frontotemporal dementia Scientists find evidence that reactive nitrogen molecules, abundant in old age, can trigger the disease process for two highly fatal conditions.
March 10, 2021
LA JOLLA, CA Scientists at Scripps Research have discovered a plausible trigger for the most common form of amyotrophic lateral sclerosis (ALS, also commonly called Lou Gehrig's disease), and a related form of dementia. The discovery could lead to better treatments for the diseases, which currently affect about 40,000 people in the US and are generally fatal.
The scientists, whose study is published in the Proceedings of the National Academy of Sciences of the USA, found evidence that key features of ALS and frontotemporal dementia can be triggered by reactive nitrogen molecules in the human brain. These reactive molecules, which naturally increase in the brain with aging, can set off a damaging process in which an important protein, known as TDP-43, clumps together and loses its function in affected brain cells.
Not only did we show how this protein can start to aggregate in lab-dish cultures, we also saw signs of this process in the brains of people who died of frontotemporal dementia, says study co-senior author Stuart Lipton MD, PhD, Step Family Foundation Endowed Chair in the Department of Molecular Medicine and founding co-director of the Neurodegeneration New Medicines Center at Scripps Research. Lipton is also a clinical neurologist who sees ALS and dementia patients.
The other co-senior author was Tomohiro Nakamura PhD, a senior staff scientist in the Lipton lab.
An enduring mystery
ALS kills neurons that control muscles, leading to a progressive paralysis that ultimately includes muscles needed for breathing. Although several well-known variants of ALS run in families and are clearly caused by gene mutations, the vast majority of cases are sporadic, arising in middle age with no clear cause.
Frontotemporal dementia, also called FTD, also usually arises in middle age with no clear cause, but can be triggered by some of the same rare gene mutations that cause familial ALS. It kills neurons in the brain's frontal and temporal lobes, altering behavior initially and later progressing to other parts of the brain to become an Alzheimer's-like dementia.
One feature that sporadic ALS and many cases of sporadic FTD have in common is the abnormal aggregation of a protein called TDP-43 within affected neurons. This protein normally works in the cell nucleus to help manage how key genes are expressed. But in ALS and certain cases of FTD, it largely disappears from the nucleus and aggregates in large, droplet-like compartments within the main body of the cell.
Many researchers suspect that the slow death of neurons in these diseases are due to this loss of TDP-43's normal function and perhaps some toxic effect of its abnormal presence outside the nucleus. But what initially triggers the protein's aggregation and disappearance from the nucleus has been an enduring mystery.
Lipton's team found evidence that this process can be caused by highly reactive molecules that contain nitrogen. These reactive molecules, which include nitric oxide, are often byproducts of cell damage or stress. Their levels are known to rise in advanced age or after exposure to some environmental toxins.
The team demonstrated in a series of experiments with cultured cells including neurons made from human stem cells that reactive nitrogen molecules can attach to TDP-43 in a process called S-nitrosylation. This causes the TDP-43 proteins to clump together and disappear from the cell nucleus. (S-Nitrosylation is the outcome of a biochemical reaction that was originally discovered in Lipton's laboratory during work on other proteins.)
The researchers also found evidence that the TDP-43 aggregation resulting from S-nitrosylation can drive a positive feedback loop in which levels of reactive nitrogen molecules in affected neurons rise higher still inducing further TDP-43 aggregation.
The team also showed that TDP-43 aggregation induced by S-nitrosylation can spread from affected neurons to other, neighboring neurons, as appears to happen in ALS and FTD.
Countering the dangerous process
The scientists observed in their experiments that neurons in which TDP-43 aggregates show signs of the loss of TDP-43's function as well as other potential causes of injury consistent with observations in ALS/FTD cases.
Moreover, neurons containing TDP-43 that were exposed to compounds inducing S-nitrosylation compounds found in some environmental pollutants started to die, whereas neurons containing a genetically modified form of TDP-43 that resists S-nitrosylation were preserved. Similarly, in a mouse model of TDP-43 spread, the researchers were able to prevent a key adverse effect of aggregation with a compound that blocks nitric oxide production suggesting again that reactive nitrogen compounds are the upstream cause of these adverse effects.
The team also studied autopsied brain tissue from people who died with FTD, and found even higher levels of S-nitrosylated TDP-43 than those seen in the cell culture experiments. Their analysis of human brains also suggested that the S-nitrosylated TDP-43 had aggregated in the same distinctive way seen in the cell-based experiments.
These findings support the hypothesis that aging or environmental factors or both can trigger ALS by increasing the levels of reactive nitrogen molecules, Lipton says. Targeting these reactive nitrogen molecules or the resulting S-nitrosylated TDP-43 may be an effective strategy for treating ALS and frontotemporal dementia.
The study, S-Nitrosylated TDP-43 triggers aggregation, cell to cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD was authored by Elaine Pirie, Chang-Ki Oh, Xu
Most recent headlines
04/08/2024
Dalet, a leading technology and service provider for media-rich organizations, is excited to announce Santiago Solanas as its new Chief Executive Officer (CEO)....
03/06/2024
Dalet, a leading technology and service provider for media-rich organizations, a...
04/05/2024
NEW YORK As the Asian Pacific American Heritage Month kicks off in May, Nielsen has released an extensive new report diving into their media habits with data sh...
04/05/2024
PHILADELPHIA As National Military Appreciation Month gets underway, Comcast has announced several new initiatives to help veterans, service members, and their f...
04/05/2024
WASHINGTON, D.C. Federal Communications Commission chairwoman Jessica Rosenworcel has announced a tentative agenda for the May Open Commission Meeting scheduled...
04/05/2024
The Broadband Forum has announced major enhancements to key 5G convergence standards that the group said will help advance next-generation applications, improve...
04/05/2024
Spotify Wrapped Campaign Spot Graded With DaVinci Resolve Studio
Brie Clayton May 3, 2024
0 Comments
Blackmagic Design today announced that Colorist M...
04/05/2024
Three Boston Conservatory at Berklee Alums Nominated for Tony Awards An additional eight alums and two current students performed in nominated productions.
...
03/05/2024
An innovative learning tool to help media and civil society better understand ho...
03/05/2024
PARK CITY, UTAH - JANUARY 21: (L-R) Actors K stutis Cic nas and Greta Grinevi i t , Director Marija Kavtaradze and Producer Marija Razgute attend the 2023 Sunda...
03/05/2024
If you aren't familiar with Danny Ocean's music, it's only a matter ...
03/05/2024
Spotify has an unwavering commitment to supporting emerging artists across all genres, to helping them launch and thrive in their careers, and to connecting the...
03/05/2024
Como uno de los sonidos de mayor expansi n en el mundo, la M sica Mexicana va m ...
03/05/2024
As one of the fastest-growing sounds worldwide, M sica Mexicana is more than jus...
03/05/2024
NEW YORK FuboTV reported that it lost 110,000 subs in Q1 2024 but it exceeded its guidance for the quarter with double digit year-over-year increases across key...
03/05/2024
Only 3 Weeks Left To Enter The Creative Industries Most Award
Brie Clayton May 3, 2024
0 Comments
Creativepool is giving a last call to the creative i...
03/05/2024
WePlay Studios Transforms the Future of Live Event Storytelling with AJA Gear
Brie Clayton May 3, 2024
0 Comments
By 2032, the esports market is expec...
03/05/2024
WASHINGTON Shannon Bream, Fox News Sunday anchor and chief legal correspondent, sat for a keynote chat at The Business of TV News, with Tom Umstead, senior co...
03/05/2024
WASHINGTON Asked how important is local news, Martha Raddatz, who has covered foreign conflicts for decades and moderated presidential debates for ABC News, s...
03/05/2024
Sony Pictures and Apollo Global Management have made a $26 billion cash offer fo...
03/05/2024
CBS announced its 2024-2025 primetime schedule, which features the new dramas NCIS: Origins, Matlock and Watson, and new comedies Poppa's House and Georgie ...
03/05/2024
Sports-focused streaming service Fubo said it reduced its red ink in the first quarter, despite losing 110,000 subscribers since the end of the year....
03/05/2024
Walmart is reportedly about to release a new 4K streaming box/smart speaker hybrid device for Google TV that could retail for as low as $50, according to a repo...
03/05/2024
Enhancements to its Delivery Workspace solution provide increased content delivery robustness and security
By Matthew Corrigan
Published: May 3, 2024
Enha...
03/05/2024
According to reports, if the bid is successful, Sony would be the significant majority shareholder of the new private company
By Jenny Priestley
Published: M...
03/05/2024
Located in Manchesters Spinningfields district, the course aims to equip students with the skills, knowledge and industry insight for a career in the creative s...
03/05/2024
Lightbridge has created a new Cine Reflect Lighting System kit, dedicated to enabling artistic lighting with consideration of today's productivity practical...
03/05/2024
Broadcast media systems integrator BeckTV and Lawo worked together on a large-scale AES67 build of radio control rooms at KPBS, San Diego's NPR and PBS memb...
03/05/2024
Raleigh, NC, April 12, 2024 SmallHD announces PageOS 6, a powerful software update free for owners of SmallHD monitors, featuring increased functionality, exp...
03/05/2024
SmallHD announces the Quantum 32 a new 31.5 OLED monitor designed to provide reference HDR/SDR images for post-production final color grading, as well as cri...
03/05/2024
By 2032, the esports market is expected to grow to $9.29 billion, bolstered by a global player count and fan following that both continue to climb. The 2023 Lea...
03/05/2024
Amagi, the global leader in cloud-based SaaS technology for broadcast and connected TV (CTV), today announced that the 11th edition of the Amagi Global FAST Rep...
03/05/2024
Riedel Communications today announced that Westdeutscher Rundfunk (WDR) is relying on a media and intercom network based on Riedel technology for the renewal of...
03/05/2024
Broadpeak , a leading provider of content delivery network (CDN) and video streaming solutions for content providers and pay-TV operators worldwide, announced t...
03/05/2024
Media technology innovator Limecraft will exhibit the latest updates to its online platform on stand G79 at the 15-16 May 2024 Media Production & Technology Sho...
03/05/2024
Audio interface specialist Prism Sound is partnering with console manufacturer Solid State Logic, professional monitor manufacturer PMC and acoustic panel and d...
03/05/2024
Intinor, Sweden's leading developer of products and solutions for high-quality video over the internet, is set to join forces with its UK partner Zest Techn...
03/05/2024
NAKIVO Inc., a fast-growing software company dedicated to protecting physical, virtual, cloud, and SaaS environments, announced its Q1 2024 financial results to...
03/05/2024
Hiltron Communications announces an addition to its range of satellite communication products and systems: a field-upgradable motorisation kit specifically desi...
03/05/2024
Visit LiveU at Stand D30
With this year an exceptional one for major sporting events alongside multiple, key elections, the power and flexibility of LiveU'...
03/05/2024
Agile Content, the leader in the development of technology and solutions for the provision of television services over the Internet, announces Koldo Unanue as i...
03/05/2024
Eight co-signers representing streaming services, pay TV operators and public interest groups have sent a letter to Congressional leaders urging their Committee...
03/05/2024
BOSTON Brightcove has announced that it has implemented Amazon Q Business, a new generative AI assistant on Amazon Web Services (AWS)....
03/05/2024
NEW YORK CBS has declared that it will finish the 2023-24 season as Americas Most-Watched Network in primetime for the 16th consecutive season....
03/05/2024
A new survey indicates that U.S. businesses and consumers had an overall positive attitude towards their technology spending plans in the first quarter of 2024,...
03/05/2024
Sony and Apollo Global Management have sent an offer letter to Paramount Global's board of directors making an $26 billion all cash offer for Paramount Glob...
03/05/2024
EMG / Gravity Media has appointed Charlie Cubbon chief operating officer (COO) and Jamie Hindhaugh regional CEO for the U.K., U.S., Australia and the Middle Eas...
03/05/2024
Final 2024 Season Games to Air Saturdays on WRAL at 10:30am in May, Championship on June 1
Taping for the final episodes of the 2024 season of WRAL-TV's Br...
03/05/2024
Estrella MediaCo said it is expanding its connected TV portfolio by launching three new channels with Curiosity that will first appear on Samsung TV Plus....
A new clue to the cause of ALS and frontotemporal dementia Scientists find evidence that reactive nitrogen molecules, abundant in old age, can trigger the disease process for two highly fatal conditions.
