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
06/10/2025
France T l visions, France's leading broadcaster, has received the 2025 EBU ...
04/09/2025
Monumental Sports & Entertainment (MSE), in collaboration with Dalet, has been a...
30/08/2025
WASHINGTON The Federal Communications Commission has adopted its FY 2025 Regulatory Fees Order that establishes the regulatory fee rates for the broadcast stati...
29/08/2025
Australian Red Cross and SBS launch training to help workplaces in the fight aga...
29/08/2025
The National Film and Video Foundation (NFVF), an agency of the Department of Sp...
29/08/2025
L3Harris Technologies has concentrated decades of expertise across the entire enterprise to develop affordable and reliable best-of-breed solutions to rapidly c...
29/08/2025
BURBANK, Calif. The CW Network and the Pac-12 Conference have announced a new media rights deal that will extend their broadcast partnership beginning with the ...
29/08/2025
NEW YORK Gracenote has released a new analysis of its global video dataset showing that the number of FAST channels grew nearly 14% from Q1 2025 and 76% since 2...
29/08/2025
SAN JOSE, Calif. Harmonic has announced a series of improvements to its live sports streaming solution that the company said will improve fan engagement, protec...
29/08/2025
NEW YORK and LOS ANGELES Fox Corp. and YouTube TV last night announced a renewal of the full portfolio of Fox networks, including Fox News Channel, Fox Business...
29/08/2025
Budapest, Hungary, August 2025 - The integration of Microsoft Teams Rooms (MTR) with Lightware's Taurus universal matrix switchers delivers a new level of f...
29/08/2025
Frequency, the engine behind many of the world's best-known streaming television channels, today announced it will launch Studio Live, a next-generation uni...
29/08/2025
In an era when AI and cyber resilience are essential, Scality will mark the 10th anniversary of Scality Day on October 16, 2025 in Paris. This flagship global e...
29/08/2025
Disguise's In-House Creative and Technical Teams Pre-Visualised, Programmed and Delivered Content for the Experience, All Powered by EX 3+
Technology solu...
29/08/2025
Disguise will be demonstrating the latest workflows for TV, film and live events on a number of partner booths at the show
Disguise, the industry-leading tech...
29/08/2025
STOCKHOLM, Sweden Accedo will showcase Accedo Compose, its AI agent-powered modular orchestration layer that assists streaming providers in transitioning client...
29/08/2025
LOS ANGELES Cineverse has announced that it is working with Xperi to bring four of its streaming channels to automobiles for the first time as part of the DTS A...
29/08/2025
DALLAS & ATLANTA Gray Media has announced an agreement with the sports streaming service Victory+ to simulcast 17 Dallas Stars NHL games in 15 television market...
29/08/2025
NEW YORK AND CULVER CITY Comcast NBCUniversal and Amazon have announced new and extended distribution agreements that will expand the content available on their...
29/08/2025
FOOTHILL RANCH, Calif. RED Digital Cinema will feature its Cine-Broadcast Module supporting live broadcast workflows during IBC2025, Sept. 12-15, at the RAI Ams...
29/08/2025
29 Aug 2025
Kyivstar Rings Opening Bell at Nasdaq Marking Landmark Listing and ...
29/08/2025
More than half of all NFL games live on Sky for the first timeFriday 29 August 2025
Sky Sports has announced a new three-year deal with the NFL, extending its ...
29/08/2025
Back to All News
RIV4LRIES: The Trailer of the New Series With Samuele Carrino ...
29/08/2025
Get ready for an inspiring and emotional insight into the world of competitive Irish dancing with My Story: Tomi Champion of the World airing on RT 2 this monda...
29/08/2025
RT has today announced that David McCullagh is to be the new presenter of RT Radio 1's flagship Today programme, which airs every weekday at 10am, replaci...
28/08/2025
By Kristin Feeley, Director, Documentary Film & Artist Programs
If you want to tell untold stories, if you want to give voice to the voiceless, you've got ...
28/08/2025
Directed by Steven Bognar and Julia Reichert, Sundance Institute-supported Amer...
28/08/2025
Corridos have been a cornerstone of M sica Mexicana for generations, telling stories rooted in everyday life. Now, a new chapter is taking shape: motivational c...
28/08/2025
Los corridos han sido un pilar de la M sica Mexicana durante generaciones, contando historias enraizadas en la vida cotidiana. Ahora, un nuevo cap tulo est tom...
28/08/2025
Earlier this month, we promised our Verano Forever party would bring the heat, a...
28/08/2025
L3Harris will provide the Polish F-16V fleet with the Viper Shield electronic warfare system as part of an upgrade program....
28/08/2025
Bilbao, August 26, 2025 - AgileTV, an international television and video technol...
28/08/2025
Ken Wilkinson is an Emmy Awards nominated New York audio engineer who specialises in production sound mixing for film, commercial, episodic and documentary work...
28/08/2025
NEW YORK FuboTV today announced that it will launch Fubo Sports, a skinny bundle that focuses on sports with a subscription price of $56 monthly....
28/08/2025
NEVADA City, Calif. At IBC2025, Sept. 12-15 at the RAI Amsterdam, Telestream will debut its new Global Ingest strategy, introducing a next-generation ingest arc...
28/08/2025
Dr. Rhoda Bernard Releases Groundbreaking Debut Book on Accessible Arts Educatio...
28/08/2025
TAG Video Systems, the leader in software-based IP end-to-end workflow monitoring, deep probing, and real-time visualization, has named Oliver Gappa as Sales Di...
28/08/2025
AI-based voice enhancement will be among a series of innovations making their IBC 2025 debut on the DHD stand B46 in Hall 8 at the RAI Amsterdam Convention Cent...
28/08/2025
Telef nica Servicios Audiovisuales (TSA), the leading system integrator and service provider in the media sector in Spain, with the support of Appear, the globa...
28/08/2025
To fully immerse sailing fans in the world's biggest offshore yacht race, production company, Optical Media turned to LiveU's On-site Production solutio...
28/08/2025
Working with Calrec on its most recent overhaul, radio and television broadcaster, WNED has migrated to a fully IP infrastructure with multiple Type R consoles,...
28/08/2025
Cleeng, the Subscriber Retention Management (SRM ) inventor, has unveiled Cleeng Pro, the first-ever direct-to-consumer (D2C) subscription management platform t...
28/08/2025
Zixi, the industry leader in live broadcast-quality video over IP, today announced that French media distribution platform OKAST has selected Zixi to enable rel...
28/08/2025
Solution offers a streamlined, speaker-free architecture to optimize integration with premium external loudspeakers and advanced loudness metering
Nixer Pro Au...
28/08/2025
Cinegy, the premier provider of software-defined television technology, has announced a strategic partnership with Vision One Touch Film Production Services L.L...
28/08/2025
Telestream, a global leader in media workflow technologies, will debut its new Global Ingest strategy at IBC2025, introducing a next-generation ingest architect...
28/08/2025
Tier 1 operator selects Broadpeak to power high-performance, unified CDN solution across Norway, Sweden and Finland
Broadpeak, a leader in streaming and moneti...
28/08/2025
Leading video software provider, Synamedia, today announced that 24 Frames Digital, one of India's leading live event streaming service providers, has chose...
28/08/2025
Meet VisualOn at IBC2025: See What's Next in AI-Powered Video Streaming Join VisualOn at IBC2025 and discover how our AI-driven Optimizer and advanced media...
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.
