Catching et al. use single-nucleus ATAC plus gene expression to profile 357 neurologically unaffected postmortem human prefrontal cortices and characterize the molecular effects of aging on different cell types. Analysis of each cell type identifies genes and chromatin regions associated with aging in the human prefrontal cortex.
This study describes a novel ATXN2 expansion within the classic pathogenic range for spinocerebellar ataxia 2 that manifests as an early-onset neurodegenerative disorder in the homozygous state, while being asymptomatic into late adulthood in the heterozygous state.
The length and content of ATXN2 trinucleotide repeat significantly influences disease development and clinical phenotype. ATXN2 alleles containing 13–31 CAG trinucleotide repeats are normal and commonly found in healthy individuals4 and over 90% of tested individuals possess an allele containing 22 CAG repeats.21 Spinocerebellar ataxia type 2 is caused by dominant alleles of 33 or more CAG trinucleotide repeats.11,22 Alleles containing 33–34 CAG repeats are considered reduced penetrance alleles, and carriers may or may not develop late onset ataxia.22 Fully penetrant alleles most commonly have 37–39 CAG repeats and are pathogenic for SCA2.11 While SCA2 alleles of 31 pure CAG repeats exhibit high instability on inheritance, it has been proposed that CAA interruptions confers meiotic stability.23 An anticipation phenomenon in SCA2 has also been described, consisting of earlier disease onset and increased clinical severity in subsequent generations which are mirrored by an increase in CAG repeat size.12 Patients with SCA2-related parkinsonism carry intermediate range alleles and possess alleles with CAA interruptions.24,25 Similarly, ATNX2 variants associated with ALS are CAA interrupted and are rarely in the pathogenic range of SCA2.26,27 Contrasting with trinucleotide expansion diseases, repeat size has no bearing on ALS AO but correlates with disease risk.28 ATXN2 has been identified as a disease modifier gene for a variety of neurologic conditions and similarly, various genes may influence the AO of SCA2, including long normal repeats in the CACNA1A and RAI1 genes.29 Nonetheless, the most important predictor of AO and clinical severity remains the polyglutamine repeat expansion size.30
Infantile and childhood forms of SCA2 are described, and these patients present with a multi-systematic neurodegenerative disorder including developmental delay, retinitis pigmentosa, optic atrophy, hypotonia, seizures, facial dysmorphism, dystonic features, and early mortality.21,31 Infantile cases all possess extreme length CAG repeats (range 69–884) in the heterozygous state, with clinical severity related to repeat size, and inherited with an anticipation phenomenon from parents within the fully penetrant range of SCA2 (range 39–47 CAG repeats).21,31
Homozygous cases of SCA2 are exceedingly rare.32,33 Notably, a patient with 31/31 CAG alleles developed late-onset cerebellar ataxia, suggesting that patients with homozygous variants may manifest signs of disease within a nonpathogenic variant range, that is not associated with disease development in the heterozygous state.18,32 Two homozygous cases from an Indian family with 35/37 and 36/39 CAG repeats alleles developed early onset, levodopa responsive Parkinson disease without ataxia,33 while several family members with heterozygous ATXN2 variants exhibited parkinsonism and/or ataxia with variable ages of onset ranging from adulthood to their sixties.33 Moreover, two homozygous cases with intermediate alleles of 32/3217 and 33/3327 displayed a pure ALS phenotype, without ataxia. These cases highlight the phenotypical variability of homozygous ATXN2 variants.
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Smaller gene-editing system could expand treatment options for cancer, ALS and other diseases.
A National Institutes of Health (NIH)-funded research team has discovered an enhanced CRISPR gene-editing system that could enable targeted delivery inside the human body — a key step toward broader clinical use. Researchers identified a naturally occurring enzyme, Al3Cas12f, that is small enough to fit into adeno-associated virus vectors, a leading targeted delivery method for gene therapies. They then engineered an enhanced version that dramatically improved gene-editing performance in human cells.
The advance addresses a major limitation in CRISPR technology. Commonly used gene-editing proteins are too large for targeted delivery systems, restricting clinical applications to cells modified outside the body, such as blood and bone marrow.
Here, Johann de Bono, Luke Gaughan & team identify the protein TRA2B as being key for the synthesis of AR-Vs.
1Newcastle University Centre for Cancer, Paul O’Gorman Building, Framlington Place, Newcastle upon Tyne, United Kingdom.
2The Institute for Cancer Research, London, United Kingdom.
3The Royal Marsden NHS Foundation Trust, London, United Kingdom.
4Newcastle University Bioinformatics Service Unit, Medical School, Newcastle University, Newcastle, United Kingdom.
Scientists have developed a new way to fight gum disease without wiping out the mouth’s helpful bacteria—a major shift from traditional treatments. Instead of killing everything, this targeted approach blocks only the harmful microbes that drive periodontitis, allowing beneficial bacteria to thrive and restore balance naturally.
The debilitating, chronic loss of joint cartilage known as osteoarthritis causes pain and bone decay for hundreds of millions of people every day, but new help may be on the way – in the form of a simple, single shot.
Based on ongoing animal experiments, injecting a carefully engineered, slow-release drug-delivery system into the damaged joint can coax the body’s own cartilage and bone cells to carry out an effective repair job in just a few weeks.
“In two years, we were able to go from a moonshot idea to developing these therapies to demonstrating that they reverse osteoarthritis in animals,” says chemical and biological engineer Stephanie Bryant, from the University of Colorado (UC) Boulder.