A familiar Alzheimer’s protein may have a hidden role in cell division.
Category: neuroscience – Page 25
Expanding the Genetic Landscape of ATXN2 VariantsInsights From a Biallelic Trinucleotide Repeat Expansion in an Acadian Family
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.
Affecting a Signaling Pathway Alleviates Alzheimer’s in Mice
A new study shows that the overexpression of somatostatin (SST), a neuropeptide produced in neurons and acting mostly on microglia, lowers inflammation and amyloid β burden, improving cognitive abilities in a mouse model of Alzheimer’s. Drugs affecting this pathway are already available [1].
The unusual suspect
In Alzheimer’s disease, many signaling pathways in the brain become dysregulated. Since going after the main hallmarks of the disease (amyloid β and tau protein accumulation) has only yielded modest results so far, scientists are exploring various secondary targets whose levels correlate with the disease.
Single-cell epigenomics uncovers heterochromatin instability and transcription factor dysfunction during mouse brain aging
Amaral et al. present a single-cell atlas of brain aging, revealing coordinated chromatin and gene expression changes across multiple regions from young to old mice. Their analyses show that aging involves loss of progenitor cells, dysregulation of master transcription factors, and destabilization of heterochromatin, driving a gradual erosion of cellular identity.
Striatal Dopamine Transporter and Rest Tremor in Parkinson DiseaseA Clinical Validation
【】 Full article: (Authored by Nader Butto, from Petah Tikva, Israel.)
This work presents a vortex-based geometric interpretation of atomic structure, in which electrons are described as localized vortex excitations embedded in a structured vacuum, offering a physically intuitive framework for understanding shells, subshells, orbitals, quantum numbers, and electron configurations without altering the formal structure of quantum mechanics. QUANTUM_NUMBERS vortex_geometry ElectronConfiguration.
The atomic structure of matter represents one of the foundational achievements of modern physics and chemistry. Early experimental investigations by Rutherford established the nuclear model of the atom [1], while Bohr introduced the concept of discrete electronic energy levels to explain atomic spectra [2]. Sommerfeld subsequently extended this picture by incorporating angular momentum quantization and relativistic corrections [3]. These developments paved the way for the formulation of quantum mechanics, which replaced classical electron orbits with a wave-based description of electronic states.
The quantum-mechanical framework, formalized through the work of Schrödinger, Pauli, Born, and Dirac, provides a mathematically rigorous and highly successful description of atomic behavior [4]-[7]. Within this formalism, electrons are described by wavefunctions whose squared modulus gives the probability density of finding an electron in a given region of space. Atomic orbitals arise as solutions of the Schrödinger equation and are characterized by a set of quantum numbers that determine their energy, angular momentum, spatial orientation, and spin. This approach accurately predicts atomic spectra, selection rules, and chemical periodicity.
The gut can drive age-associated memory loss, research reveals
While it seems logical that age-related cognitive decline would be blamed on brain aging and degeneration (which, like anything in the brain, is notoriously hard to treat), there’s some evidence that processes elsewhere in the body influence the brain’s ability to form memories. In particular, neuronal pathways that sense the status of other organs in the body can influence cognitive functions in the brain.
Other studies have shown that our gut microbiome affects learning, memory, and behavior. But what we don’t yet understand is how these connections work—the specific molecules, microbes, and gut-brain communication involved—and whether we can use that knowledge to prevent or reverse age-related memory loss.
In our new work published today in Nature, we discovered that the aging gastrointestinal tract produces specific molecules that blunt the activity of a key gut-brain neuronal pathway, leading to age-related cognitive decline in mice.
The brain’s default mode network splits into ‘sender’ and ‘receiver’ zones, study finds
The default mode network (DMN) is a distributed set of interconnected brain regions that has long been associated with internally oriented cognition, such as remembering the past, thinking about the future, or thinking about oneself. Accumulating evidence also indicates that the DMN is engaged during tasks involving external perceptual input, such as language comprehension and social perception. However, the mechanism by which the same network supports both internally and externally oriented cognition has remained unknown.
Now, a research team led by Zhang Meichao from the Institute of Psychology of the Chinese Academy of Sciences (CAS) has identified an organizational principle within the DMN that helps explain how the network supports both internal and external cognition.
The study, published in PNAS, reveals that distinct subregions within the DMN act as “senders” and “receivers” of information, enabling flexible shifts between perception and memory-driven thought.
