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Category: genetics

Tau mutation drives autophagy-lysosome dysfunction

The researchers studied a specific mutation in a brain protein called tau that causes the protein to become misfolded and alter its normal function. In general, when tau proteins become misfolded, they build up inside neurons and contribute to various forms of dementia, including Alzheimer’s dementia and frontotemporal dementia, a neurodegenerative disease similar to Alzheimer’s that often strikes earlier — in middle age — and typically involves significant changes in personality and behavior that precede cognitive decline.

In this new study, the researchers studied neurons that had been reprogrammed from skin cells sampled from patients with frontotemporal dementia who carried the tau mutation. In the neurons, the mutated tau proteins caused waste-recycling centers called lysosomes, which are involved in autophagy, to become dysfunctional, allowing cellular waste to accumulate in the lysosomes, which may contribute to neuronal death. The researchers found that enhancing autophagy with an analog of the chemical compound G2 improved clearance of the garbage, reduced tau levels in the lysosomes and prevented cellular toxicity and death.

G2 was discovered in 2019 via screening experiments seeking drugs that could reduce the accumulation of an aggregation-prone protein in a C. elegans model of alpha-1-antitrypsin deficiency, which can cause severe liver disease. The compound was later shown to boost autophagy function in mammalian cell model systems.

The researchers also have shown that G2 can protect brain cells from death in cells modeling Huntington’s disease, a fatal inherited neurodegenerative disease caused by a genetic mutation present at birth. In the cellular model of Huntington’s disease, the compound prevented the buildup of a harmful RNA molecule. ScienceMission sciencenewshighlights.

New research adds to growing evidence that helping brain cells break down and eliminate their own cellular waste is a promising treatment strategy for a variety of neurodegenerative diseases. In lab experiments, the researchers found that exposure to a novel compound can clear a harmful protein from human neurons modeling frontotemporal dementia — a devastating and ultimately fatal condition — and prevent those neurons from dying.

The study is published in the journal Nature Communications.

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Lab-grown pineal gland organoids produce melatonin, offering a new sleep model

Organoids are miniature, simplified versions of an organ. Over the past two decades, scientists have developed them for the gut, lung, liver, mammary gland, brain, and more. Now, researchers at Yale School of Medicine (YSM) have organoid-ized the pineal gland, a small structure in the brain that regulates sleep patterns through its production of the hormone melatonin.

In a study published in Cell Stem Cell, the researchers demonstrate how pineal gland organoids can be used to study sleep dysfunction in conditions like Angelman syndrome, autism, and depression.

“In a number of neuropsychiatric conditions, severe sleep problems are a major symptom,” says In-Hyun Park, Ph.D., associate professor of genetics at YSM and senior author of the study. “With pineal gland organoids, we may be able to uncover the causes of those sleep disturbances and possibly identify treatments.”

Mapping mutations at scale in a single gene reveals new neurodevelopmental condition

The ability of different genetic variants—changes to one or more building blocks of DNA—to cause disease, and to what extent, has historically been opaque. Geneticist and Crick group leader Greg Findlay has pioneered a new method in the hope of changing this. Called “saturation genome editing,” the new technique involves mapping every single variant in a given gene to work out what it does and pinpoint which changes are responsible for specific disorders.

While Greg was refining these experiments, Nicky Whiffin, associate professor at the University of Oxford, had identified that mutations in a tiny gene were behind a rare inherited neurodevelopmental disorder, known as ReNU syndrome, which impacts brain function, development and motor skills. Children develop this syndrome if a single copy of the RNU4-2 gene is mutated in a specific way.

Nicky initially found that several distinct mutations in a critical region of the gene caused the condition, and she was keen to understand if some of these genetic variants led to more severe disease.

Histone modification clocks for robust cross-species biological age prediction and elucidating senescence regulation

Building upon these insights, we constructed 36 histone modification-based epigenetic clocks, which exhibited robust predictive accuracy (mean Pearson’s r = 0.91) across multiple tissues and marks. Among these, the blood-derived H3K27ac clock emerged as a particularly powerful model, outperforming several established DNA methylation clocks under matched conditions. This performance is remarkable considering that DNA methylation clocks have undergone extensive optimization over the past decade (9, 16, 18), while our histone-based approach represents a first-generation effort.

A distinctive advantage of our histone-based clocks is their resilience to technical and biological noise. When exposed to artificial Gaussian noise, the histone-based clock maintained stable predictive performance, in contrast to the sharp degradation observed in many methylation-based models. This robustness is likely attributable to the broader, structural nature of histone mark signals, which may be less sensitive to local fluctuations than single CpG methylation values. This characteristic makes histone clocks potentially more suitable for noisy, heterogeneous, or clinically derived datasets where sample quality may vary.

The practical utility of our histone-based clocks was further demonstrated by their ability to detect biological age acceleration in leukemia samples and capture age reversal following therapeutic interventions. These applications highlight the potential of histone-based clocks as biomarkers for disease states and treatment responses, offering a complementary approach to existing clinical tools.

APOE4 Increases Neurons’ Excitability Before Symptoms Appear

The pro-Alzheimer’s allele APOE4 makes hippocampal neurons in mice smaller and hyperexcitable. This effect, which resembles epilepsy and accelerated aging, can be mitigated by manipulating a neuronal protein [1].

Before symptoms arise

Alzheimer’s disease begins long before symptoms appear, building silently for decades. The single strongest genetic risk factor for the common, late-onset form of Alzheimer’s is the ε4 variant of the apolipoprotein (APOE) gene, APOE4. Carrying a single copy of this variant (being heterozygous) roughly triples your Alzheimer’s risk; having two copies increases it about 12-fold.

How an Alzheimer’s Risk Gene Disrupts Brain Circuits Long Before Memory Loss

Researchers at the Gladstone Institute have uncovered the molecular mechanism by which APOE4 — the most significant genetic risk factor for Alzheimer’s disease, present in roughly a quarter of the population — begins damaging neural circuits well before any cognitive symptoms emerge. Studying young mice carrying the APOE4 variant, the team found that the gene triggers overproduction of the protein Nell2, which causes neurons to shrink and become hyperactive. Crucially, the degree of early neuronal hyperactivity predicted the severity of memory impairment later in life, even in animals that still showed normal learning and memory at the time of measurement. Strikingly, targeting Nell2 therapeutically was able to reverse these changes even in adult animals, demonstrating that the neurodegeneration is not irreversible and that a window for intervention may exist even after the disease process has begun. The team is currently continuing preclinical testing of this therapeutic strategy.

New findings on the APOE4 gene variant point to a potential therapeutic target for Alzheimer’s disease. From left to right, Gladstone scientists Misha Zilberter, Yadong Huang, and Dennis Tabuena examine findings from their research, which is published in the journal Nature Aging.

For the millions of people who carry the gene APOE4, the strongest known genetic risk factor for Alzheimer’s disease, their brain activity may begin changing long before any memory problems appear. Now, researchers at Gladstone Institutes have uncovered a precise chain of molecular events behind those early changes and identified a potential way to reverse them.

Published in the journal Nature Aging, their new study in mouse models reveals how APOE4 triggers increased production of the protein Nell2, which makes neurons shrink and become hyperactive. The more hyperactive the neurons were in early life, the more severe were the memory problems the mice developed later in life.

Optogenetics, Biohybrid Implants And The Future Of Brain-Computer Interfaces | Dr. Alan Mardinly

Optogenetics, Biohybrid Implants And The Future Of Brain-Computer Interfaces — Dr. Alan Mardinly Ph.D. — CSO & Co-Founder, Science

What if we could restore vision, communicate directly with the brain, and even extend human life—not with machines alone, but with living, engineered biology?

Dr. Alan Mardinly, Ph.D. is the Chief Scientific Officer and Co-Founder of Science Corp. (https://science.xyz/), a neurotechnology company developing next-generation brain interfaces and biohybrid neural implants aimed at restoring human function.

Dr. Mardinly leads the company’s biohybrid program, focused on combining genetically engineered cells with advanced optical hardware to create optogenetic therapies for vision restoration and new types of brain-machine interfaces.

Dr. Mardinly has spent more than 15 years working at the intersection of neuroscience, genetics, and neural engineering.

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