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Toxic Clumps in Huntington’s Disease May Protect the Brain Too
The findings could lead to new treatments for multiple neurodegenerative diseases.
Huntington’s disease is tragically predictable. An inherited genetic mutation causes neurons to make distorted, sticky proteins. These proteins clump together and gradually overwhelm brain cells. The brain loses its ability to learn, remember, and make decisions.
This story is dogma in neuroscience. But decades of research and drugs targeting the clumps have had little success. Scientists are now wondering: Is there more to the story? In a twist, a team from the Hebrew University of Jerusalem and collaborators found that protein clumps may be a neuron’s first line of defense against damage.
The misfolded or malfunctioning proteins are quarantined inside bubbly hubs called “inclusion bodies.” Often considered detrimental to cell health, disrupting their formation unexpectedly led to cells becoming more sensitive to stressors often seen in neurodegenerative diseases.
Physical separation played just one part. Inclusion bodies also changed the activity of genes involved in neuroinflammation—even in the absence of immune cells. Scouting the genetic landscape of cells derived from patients with severe Huntington’s disease, the team homed in on a “master regulator” gene, ATF3, that orchestrates immune responses. Removing the gene lessened inclusion bodies’ protective effects against damage in cultured cells.
To be clear, the findings are only for a cell model of Huntington’s disease in a petri dish. And inclusion bodies could be a double-edged sword: protective in the beginning and detrimental later on. Still, acknowledging them as a more complicated villain could better inform strategies for disorders that take over our minds like Huntington’s.
“Our results reveal…that these structures are not merely byproducts of disease, but a central factor in the cell’s ability to mount a protective response against stress,” said study author Eran Meshorer in a press release.
The Problem With PolyQIt’s long been believed that protein clumps in the brain gradually erode cognition. Whether they’re the main driver of neurodegenerative disorders is still debated, but their presence accelerates brain cell injury, causing neurons to wither away.
Alzheimer’s disease, for example, is associated with two sets of protein clumps. One lives inside neurons (tau) and another gunks up the space between cells (amyloid). Decades of research aimed at removing amyloid clumps have met with minimal success, earning these doomed efforts the notorious nickname “graveyard of dreams.” Despite their struggles, the FDA recently approved two major drugs that remove amyloid clumps and modestly slow cognitive decline, though the approval has been controversial due to doubts about safety.
Other untreatable neurodegenerative disorders also fall into this category. Clumps formed in Parkinson’s disease erode the brain’s ability to control movement, emotion, and even the perception of time. Lou Gehrig’s disease, or ALS, produces inclusion bodies inside motor neurons, leading to muscle weakness and trouble swallowing. The disease eventually robs people of speech and motion.
These diseases often have multiple genetic and environmental triggers. Huntington’s, in contrast, is entirely genetic. The condition stems from the genome over-copying parts of the huntingtin gene (HTT), which normally makes a key protein also called huntingtin.
Normally, cells use the protein’s large, stackable structure to build highways that transport all sorts of biological cargo, from molecules to organelles. The protein also plays an essential role during early brain development and neural wiring in adulthood.
But a mutant form of the HTT gene can wreak havoc. A common mutation, called polyQ expansion, produces unwieldy, misfolded proteins. Nearly 30 years ago, researchers found that these errant proteins aggregate inside parts of the cell. The clumps, or inclusion bodies, were widely thought to be detrimental. Some act like sticky tape that captures healthy proteins, such as those involved in gene expression, and torpedoes cellular health.
But telltale signs in cultured rat brain cells suggest a more nuanced story: Inclusion bodies could also be protective, sequestering mutant proteins as an early form of protection.
A Tale of TwoThe common factor in diseases featuring polyQ mutation is repetition. Mutated genes have long, duplicated sequences of the DNA letters cytosine, adenosine, and guanine (CAG). More CAG repeats in the genome translates into earlier disease onset.
We all have this DNA triplet in our HTT gene. But more than 39 repeats results in longer, toxic huntingtin proteins. Severe cases of Huntington’s can feature over 100 CAG repeats, transforming the usually free-floating protein workers into sticky, dysfunctional layabouts.
In the new study, the researchers first established a baseline. They used the gene editing tool CRISPR-Cas9 to reduce CAG repeats in cells derived from Huntington’s patients—which carried over 180 copies—to near normal levels.
They then tagged the cells with a fluorescent marker that causes huntingtin proteins to glow bright green under the microscope. This let the team track protein aggregation in real time. Though they shared the same genetics, some cells formed inclusion bodies; others didn’t.
The team next challenged them with a chemical known to cause cellular stress. Those that formed clumps survived far more regularly than those that didn’t. It was a “striking difference,” the authors wrote. “Once a mutant PolyQ protein is expressed, the formation of IBs [inclusion bodies] protect[s] the cells rather than inflict[s] harm, at least short-term.”
Inflammation seems to be key. Although grown side-by-side, a genetic screen revealed cells with inclusion bodies were especially abundant in a gene called ATF3, which is known to regulate inflammation. Getting rid of the gene wiped out the neurons’ ability to form inclusion bodies, making them more vulnerable.
“Our results reveal a previously unknown role for ATF3 in orchestrating the formation of inclusion bodies in human neurons,” said Meshorer.
These are very early results. An immune molecule bridges ATF3 and inflammation and is associated with Huntington’s disease. Its levels are higher in patients with the condition. Increasing ATF3 activity could amp up the number of protective inclusion bodies and give neurons a fighting chance.
The findings suggest inclusion bodies gather free-floating mutant proteins into clumps to protect neurons and reduce brain damage—at least at the beginning of the disease. However, lab experiments rarely translate to treatments. How fast inclusion bodies form and when they begin to stress cells remains to be seen. Meanwhile, a gene therapy for Huntington’s is underway, and promising results in a small trial suggest an alternative path for treatment.
Still, the study challenges the idea that protein clumps are always detrimental. If replicated in other neurodegenerative diseases such as Alzheimer’s or ALS and if we can learn how long protection lasts, the results could pave the way for better-timed treatment that works with the body’s protection, not against it.
The post Toxic Clumps in Huntington’s Disease May Protect the Brain Too appeared first on SingularityHub.
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Why Apple may be winning again
As we lean into WWDC, three strategically brilliant Apple moves have been exposed in the last couple of weeks, two of which will have immense consequences in the coming year, while one sets the scene for essential future growth.
In each case, Apple’s leadership has found counter-intuitive gambits that actually secure the company’s future. Let’s start with Vision Pro.
It came from the futureNews this week is that incoming CEO John Ternus has made some tough decisions around Apple’s approach to spatial computing, terminating development of Vision Pro (even as leaked images of a black model emerge) while focusing R&D on two smart glasses projects to compete with Meta.
The intention is to introduce XR and AR glasses priced at around $300 to $500 each. While not as richly-featured as the Vision Pro, they will be within the reach of more people and draw deeply on the huge R&D effort that went into the original Apple AR visors. Apple hopes a focus on trust and privacy will be enough to push Meta aside, helping Cupertino dominate this part of the category. If that plan succeeds, don’t be at all surprised to see plans for Vision Pro 2 return to the table, though that’s not the focus now.
Apple frequently described the Vision Pro as a product “pulled from the future,” a device for enterprise users and early adopters. For many such users, the existing product will be useful in their work for time to come.
What’s strategically solid about this is that Apple has now defined a good future for spatial computing and is bringing components of that future to the mass market on the basis of a provable technology you can already try for yourself in any Apple Store. This is a long game, and while it will take time to play out, it’s a game the company has proved it can join.
Privacy as a standardApple has apparently chosen to use Nvidia and Google technologies to support at least some of the Apple Intelligence/Siri improvements to be announced at WWDC next week. This seems to fly against the company’s general approach to privacy on its platforms, with the silicon, operating system and — thanks to Private Cloud Compute — the cloud all in its control.
How, you might ask, can Apple ensure privacy when using third-party infrastructure to manage some AI transactions? How can it do so without damaging its trusted brand?
One direction that makes sense is to consider that Apple and its partners have reached consensus on what privacy should be and how it should be delivered. That’s a very important consensus, as it suggests Apple is building an approach that makes privacy an attestable standard.
The company has been pushing governments for years to agree to such standards, but all it seems to have had in return are continued government attempts to erode personal privacy. That’s particularly evident in the UK government’s egregious move to undermine encryption to the detriment of all. (The UK isn’t really alone in preferring surveillance above liberty.)
Android developer Google has had the same experience, and while its approach to privacy differs from Apple, both companies understand the need for encryption. As such, any form of consensus on some form of privacy standards is welcome — and while I’d very much prefer an enforceable, verifiable approach, some industry agreement has to be better than nothing at all.
While I don’t believe Apple’s approach to privacy in the new breed Siri/Apple Intelligence will be introduced in this way at WWDC, it will be interesting to see what does emerge from the new tech triptych (Apple, Google, Nvidia) in the coming months. Certainly, all three have a great interest in guarding encryption against Quantum attacks for which hidden backdoors would be easy pickings.
Winning the PC WarApple has won the PC war.
- MacBook Neo is selling in such vast quantities; IDC had to boost its laptop market growth forecast even while predicting a huge Windows PC sales decline.
- Competitors are churning out products they’re marketing as MacBook Neo competitors, even though many reviewers note higher prices and lower build quality.
- Rapid component price increases, particularly around memory, are prompting some Neo competitors to come with just 8GB of RAM.
That last point needs explanation: Apple’s entry-level MacBook Neo also has just 8GB RAM, but it also has custom-designed Apple processors and an operating system optimized to run on the hardware. That means those Macs use memory far more efficiently than their competitors.
So, you can pick up some mass market Windows laptops for $800 that hold just 8GB memory, or spend $699 for a MacBook Neo with double amount and that can also run Windows in VM extremely well.
Component prices are not going to shrink back for a while, any more than further magical thinking is going to end the war in Iran. At this point in the cycle, Apple has the PC market advantage. Millions are purchasing its entry-level Mac and the vast majority of those new users will love the platform, as new users usually do. That’s going to lead to a spike in Apple services sign-ups, and prompt solid future upgrade and accessory sales cycles.
Apple accomplished this by selling a low-cost Mac at a time when competitors face existential problems maintaining their grip on the mid-range market. The longer Apple holds prices on the device, the greater the advantage it builds, while applying huge pressure on PC competitors.
Summing up the goodsWith the Mac hitting its iPod moment as it achieves mass market sales, Apple finally seeing something like progress in its attempt to secure privacy in a digital age, and a strong position from which to grow in the wearables market, the company has played a fine hand.
That’s even before it introduces us to its improved Apple Intelligence, and an era of AI access in which many everyday tasks take place token free directly on the device. Indeed, when it comes to AI, if it gets things right at WWDC, Apple appears to be making money, while AI competitors are bleeding financial oxygen as their inflated bubble heads to its inevitable demise. What about the enterprise? Take a look at this chart.
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Anthropic suggests slowing AI research until we can align it with human goals
AI could soon lead to systems capable of improving their own performance faster than humans can effectively supervise them, reviving concerns about the industry’s longstanding “alignment problem,” ensuring AI systems reliably pursue human goals, senior Anthropic researchers have warned in a new blog post titled “When AI builds itself.”
Anthropic Institute lead Marina Favaro and Anthropic co-founder Jack Clark outlined three possible futures: growth in AI capabilities may flatten out; AI efficiency gains may continue to grow, but expose bottlenecks elsewhere in software development; or AI systems may become capable of full recursive self-improvement, and build their successors by themselves. It’s that third scenario that’s prompting them to suggest society be ready to hit the brakes on AI development.
“How the alignment problem gets solved — or not — in this future is something we are least certain about,” they wrote. Advanced, self-improving models could follow our needs and wants — or, they warned, “The rare occurrences of misalignment present in today’s models could compound as the models build their successors, growing more frequent but less understood until we lose control of them. It’s possible that we can’t build, integrate, and verify the tools that we’d need to understand which trendline we are actually on.”
While Anthropic’s warning is framed around future AI development, analysts say it highlights governance questions enterprises are already beginning to confront as autonomous AI agents move from answering questions to taking actions.
“The issue is no longer just whether AI gives the right answer, but whether autonomous systems take the right action, at the right time, within the right authority,” said Ashish Banerjee, senior principal analyst at Gartner.
From model governance to agent governanceThe warning comes amid growing enterprise investment in agentic AI.
Gartner predicts that by 2028, 15% of day-to-day work decisions will be made autonomously through agentic AI and that one-third of enterprise software applications will incorporate agentic AI capabilities. The firm has also warned that governance shortcomings are already emerging, predicting that 40% of enterprises will demote or decommission autonomous AI agents by 2027 after governance failures become apparent in production environments.
Banerjee said many organizations continue to approach AI agents as advanced productivity tools when they increasingly resemble digital workers operating with delegated authority.
“CIOs should stop treating AI agents as smarter chatbots,” he said. “They are becoming digital workers with delegated authority — and must be governed like privileged users, not productivity tools.”
As agents gain the ability to conduct research, write code, invoke tools, trigger workflows, and make recommendations, enterprises face new risks around unauthorized actions, accountability gaps, data exposure, tool misuse, and insufficient auditability, Banerjee said.
“Human-in-the-loop is not a strategy if the human cannot keep up with the loop,” he said.
Charlie Dai, vice president and principal analyst at Forrester, said Anthropic’s concerns mirror challenges enterprises are already encountering as AI systems gain greater autonomy.
“Alignment becomes operational,” Dai said. “It is about ensuring agents consistently act within policy, not just model accuracy.”
Current governance approaches focus largely on models and data, but increasingly autonomous agents require oversight of runtime behavior, permissions, tool usage, and decision boundaries, Dai said.
Concerns about agent oversight are not limited to AI vendors and industry analysts.
In AI Agent Governance: A Field Guide, researchers from Institute for AI Policy and Strategy warned that “society is largely unprepared for this development” and said “the exploration of agent governance questions and the development of associated interventions remain in their infancy.” The paper argues that advances in autonomous AI agents are outpacing the governance mechanisms needed to oversee them.
Both analysts argued that governance frameworks originally designed for generative AI models may prove insufficient for increasingly autonomous systems. Dai said organizations will need greater oversight of runtime behavior, permissions, tool usage, and decision boundaries as agents become more capable.
Why Anthropic is worriedAnthropic’s researchers argue that those governance questions could become significantly harder if AI systems become increasingly involved in the process of AI research and development itself.
Favaro and Clark stopped short of predicting that fully autonomous recursive self-improvement is inevitable. Instead, they argued that the possibility warrants preparation and discussion among developers, policymakers, and other stakeholders. They also suggested the industry may eventually need mechanisms to slow development if capabilities begin advancing faster than safeguards, while acknowledging that such measures carry risks of their own.
“But if a slowdown simply lets the least cautious actors catch up technologically, it could leave everyone less safe,” they wrote in the blog post.
Forrester’s Dai said the practical implication for enterprises is that governance can no longer depend primarily on human review.
“Supervision becomes architectural, not manual,” he said. Organizations will increasingly need bounded autonomy, embedded guardrails, verifiable execution mechanisms, and fallback controls designed into agentic systems from the outset.
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