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At least 19 recordsLinked to original sources
PubMed2025

Recurrent patterns of widespread neuronal genomic damage shared by major neurodegenerative disorders.

Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) are common neurodegenerative disorders for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 429 neurons from three C9ORF72 ALS, six C9ORF72 FTD, seven AD, and twenty-three neurotypical control brains revealed significantly increased burdens in somatic single nucleotide variant (sSNV) and insertion/deletion (sIndel) in all three disease conditions. Mutational signature analysis identified a disease-associated sSNV signature suggestive of oxidative damage and an sIndel process, affecting 28% of ALS, 79% of FTD, and 65% of AD neurons but only 5% of control neurons (diseased vs. control: OR=31.20, p = 2.35×10-10). Disease-associated sIndels were primarily two-basepair deletions resembling signature ID4, which was previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Duplex sequencing confirmed the presence of sIndels and identified similar single-strand events as potential precursor lesions. TOP1-associated sIndel mutagenesis and resulting genome instability may thus represent a common mechanism of neurodegeneration.

Journal Article↗
PubMed2026

Histone deacetylases: From acetylation homeostasis to oncogenic and neurodegenerative disorders.

Histone deacetylases (HDACs) are central regulators of acetylation homeostasis, governing chromatin architecture, transcriptional dynamics, and diverse cellular processes through reversible lysine deacetylation. Dysregulation of HDAC activity disrupts epigenetic balance and is strongly implicated in oncogenic transformation and the progression of neurodegenerative disorders. This chapter provides a comprehensive overview of HDAC biology with a particular emphasis on experimental and analytical methodologies used to investigate their function. We describe the structural and functional diversity of HDAC classes and their roles in multiprotein complexes that regulate gene expression and cellular signaling. A major focus is placed on screening-compatible and mechanistic assays, including fluorometric, colorimetric, radiometric, fluorescence polarization, TR-FRET, AlphaScreen/AlphaLISA, and differential scanning fluorimetry approaches for quantitative measurement of enzymatic activity and inhibitor profiling. In addition, advanced methodologies such as mass spectrometry-based acetylome analysis, chromatin immunoprecipitation sequencing (ChIP-seq), recombinant enzyme assays, and cell-based reporter systems are discussed in the context of functional genomics and drug discovery. The integration of high-throughput screening, structural biology, and multi-omics strategies is highlighted as essential for dissecting HDAC-mediated regulatory networks. Collectively, this chapter serves as a methodological framework for studying HDAC function and developing targeted epigenetic therapies in cancer and neurodegenerative diseases.

Histone Deacetylases↗
PubMed1978

Familial neurodegenerative disorder associated with raised urinary vanillylmandelic acid.

We report a child who presented with a progressive neurological disorder associated with hypertension and paroxysms of irritability and sweating in whom an abnormality of catecholamine metabolism or excretion was demonstrated. An elder sister died at the age of 2 1/2 years with similar clinical symptoms but without blood pressure or catecholamine excretion being recorded. The exact mechanism of the disturbance of catecholamine excretion was not identified in our patient but some slight improvement in hypertension and arrest of his neurological deterioration was noted when he was put on a low tyramine diet. It is suggested that our patient may well suffer from a familial neurodegenerative disorder in which an abnormality of catecholamine metabolism or excretion is a feature.

Humans↗
PubMed2026

Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders.

Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) represent two major categories of neurodegenerative disorders-TAR DNA-binding protein 43 (TDP-43) and tau proteinopathies-for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 469 neurons from C9ORF72 ALS, C9ORF72 FTD, AD, and control brains revealed increased somatic single-nucleotide variants (sSNVs) and insertions/deletions (sIndels) in all three diseases. Mutational signature analysis identified a disease-associated sSNV signature consistent with oxidative damage and an sIndel process affecting 22% of ALS, 76% of FTD, and 61% of AD neurons-but only 2% of control neurons-resembling signature ID4, previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Rapid approach to DNA adduct recovery (RADAR) assays confirmed increased TOP1-DNA covalent complexes, and duplex sequencing confirmed the increased sIndels and identified single-strand events as likely precursor lesions. TOP1-associated sIndel mutagenesis and genome instability thus represent a mechanism shared by both TDP-43 and tau neurodegeneration.

Humans↗
PubMed2026

Progress towards a biotypic biomarker profile for amyotrophic lateral sclerosis-frontotemporal spectrum disorders.

Determining the optimal timing of disease-modifying therapies for neurodegenerative disorders will necessitate identification of when the underlying pathobiological process becomes active, well in advance of the point at which clinical manifestions appear. Phenoconversion, the emergence of clinically manifest syndomes, may be preceded by years to decades of silent pathobiological activity that can only be mapped by an array of biomarkers. ALS and FTD, traditionally identified as distinct clinical syndromes, are increasingly recognized to exist along a spectrum of clinical syndromes with shared genetic risk and shared underlying pathology. This clinicopathological spectrum is underpinned by cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) as the common neuropathological hallmark. In contrast, the majority of neuropathologically-defined frontotemporal lobar degeneration (FTLD) is associated with alterations in either TDP-43 metabolism (FTLD-TDP) or of the microtubule associated protein tau (FTLD-tau), with a smaller percentage associated with either autosomal dominant genetic mutations or impairments in the ubiquitin proteasome system. As the field of neurodegenerative disorders increasingly shifts towards the frameworks of a pathobiological definition of disease, there is a growing imperative to develop biomarkers that reflect the varied pathobiologies that underly these disorders, and to determine the sensitivity of such biomarkers to detect the presence of these pathobiologies before phenoconversion. To that end, an international workshop was convened in London, Canada in 2025 to review the evidence for existing or evolving biomarkers suitable for (1) the detection of either ALS or FTD pathobiology prior to phenoconversion and/or (2) predict phenoconversion in at risk individuals. Such biomarkers might be conceptualized as "biotypic biomarkers", capturing their ability to describe an underlying pathophysiology whilst being agnostic to the emergent clinical manifestations. Whereas no single biotypic marker is yet able to predict the emergence of ALS, FTD or their intersection, a multimodal approach to developing a biotypic biomarker profile holds promise for the detection of relevant pathobiological processes. The strength of such an approach would be augmented by also addressing issues of resiliency/susceptibility both in terms of genetic risk susceptibility profiles and developing sensitive biomarkers of genomic and cellular aging. By including such nontraditional markers of disease, a more robust picture of not only the degenerative process but also of those factors that might potentially mitigate or drive a heightened probability of disease can be derived.

cryptic exons↗
PubMed2026

A De Novo 16p13.3 Triplication Underlying Early-Onset Complex Neurodegeneration.

BACKGROUND: Neurodegenerative disorders are clinically and genetically heterogeneous, characterized by progressive neuronal loss and multidomain functional decline. Despite a presumed genetic etiology, a substantial proportion of cases remain molecularly undiagnosed. OBJECTIVE: The aim was to identify the genetic cause of an early-onset neurodegenerative disorder presenting with ataxia and cognitive impairment. METHODS: Rare copy-number variants were detected via short-read whole-genome sequencing (WGS), with candidate structural models inferred using long-read WGS. We performed transcriptomic profiling of peripheral blood leukocytes by RNA sequencing, with validation using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RESULTS: We identified a de novo copy-number gain at 16p13.3. Combined copy-number profiling and long-read WGS suggested a candidate model comprising a triplicated segment in tandem with a proximal duplication, joined to a distal duplication via an inverted junction. Transcriptomic analysis demonstrated significant upregulation of ATP6V0C, AMDHD2, and PDPK1. CONCLUSIONS: These findings support a role for structural variation in early-onset neurodegeneration and highlight the value of combining short-read copy-number profiling with long-read WGS to detect and characterize complex genomic rearrangements. © 2026 International Parkinson and Movement Disorder Society.

16p13.3↗
PubMed2026

Mitochondrial resilience: a convergent framework for pathogenesis and neuroprotection in Parkinson's disease.

Parkinson's disease (PD) is traditionally described as a dopaminergic neurodegenerative disorder driven by α-synuclein aggregation and selective neuronal loss in the substantia nigra pars compacta. While this characterization captures the core clinical and pathological features, it does not fully explain disease initiation and progression. Converging evidence from human genetics, cellular and structural biology, and systems neuroscience now supports a unified framework in which PD results from the progressive erosion of mitochondrial resilience. Here, mitochondrial resilience denotes the capacity of neuronal mitochondrial networks to withstand stress and recover bioenergetic and cellular homeostasis through coordinated quality control, metabolic adaptation, and organelle communication. Rare, high-impact monogenic mutations in PINK1, PRKN (encoding Parkin), PARK7 (DJ-1), LRRK2, and SNCA, along with common risk variants identified in genome-wide association studies, converge on interconnected pathways that govern mitochondrial quality control, bioenergetics, organelle dynamics, and cellular stress responses. These vulnerabilities are most pronounced in the highly energetic dopaminergic neurons of the substantia nigra, where sustained calcium cycling, high bioenergetic demand, and environmental stressors increase cellular susceptibility. Research has moved beyond early observations of respiratory chain impairment and oxidative stress to reveal context-specific disruptions in PINK1/Parkin-mediated mitophagy, lysosomal trafficking, mitochondrial-derived vesicle dynamics, and neuroimmune signaling. This integrated framework reframes PD as a disorder of impaired cellular maintenance rather than solely a consequence of late-stage degenerative processes. It provides a translational shift from mechanism-based biomarkers to early detection of mitochondrial failure and supports therapeutic strategies aimed at restoring mitochondrial function and resilience, offering a direct route to disease-modifying neuroprotection in PD and potentially other neurodegenerative disorders.

LRRK2↗
PubMed2024

Integrated multi-omics approaches reveal the neurotoxicity of triclocarban in mouse brain.

Triclocarban (TCC) is an antimicrobial ingredient that commonly incorporated in many household and personal care products, raising public concerns about its potential health risks. Previous research has showed that TCC could cross the blood-brain barrier, but to date our understanding of its potential neurotoxicity at human-relevant concentrations remains lacking. In this study, we observed anxiety-like behaviors in mice with continuous percutaneous exposure to TCC. Subsequently, we combined lipidomic, proteomic, and metabolic landscapes to investigate the underlying mechanisms of TCC-related neurotoxicity. The results showed that TCC exposure dysregulated the proteins involved in endocytosis and neurodegenerative disorders in mouse cerebrum. Brain energy homeostasis was also altered, as evidenced by the perturbation of pyruvate metabolism, TCA cycle, and oxidative phosphorylation, which in turn caused mitochondrial dysfunction. Meanwhile, the changing trends of sphingolipid signaling pathway and overproduction of mitochondrial reactive oxygen species (mROS) could enhance the neural apoptosis. The in vitro approach further demonstrated that TCC exposure promoted apoptosis, accompanied by the overproduction of mROS and alteration in the mitochondrial membrane potential in N2A cells. Together, dysregulated endocytosis, mROS-related mitochondrial dysfunction and neural cell apoptosis are considered to be crucial factors for TCC-induced neurotoxicity, which may contribute to the occurrence and development of neurodegenerative disorders. Our findings provide novel perspectives for the mechanisms of TCC-triggered neurotoxicity.

Animals↗
PubMed2025

Purkinje cell development and degeneration in the spastic Han-Wistar rat model of ataxia.

Hereditary ataxia is a neurodegenerative disorder notable for its early onset, with symptoms appearing in patients as young as two years old. Although affected individuals exhibit severe motor deficits and early mortality rates, the timeline of Purkinje cell loss remains unclear. To address this gap, we used the spastic Han-Wistar rat model, which harbors an unknown homozygous recessive variant that causes Purkinje cell loss. Here, we aimed to determine the onset and temporal progression of Purkinje neuronal loss in the spastic Han-Wistar model. To achieve this, we employed immunohistochemistry, Hematoxylin and Eosin histology, and neuronal density quantification. Behavioral testing demonstrated early-onset, progressive motor impairment in mutant rats, which coincided with a gradual loss of Purkinje cells in the cerebellum. Additionally, guided by pedigree analysis from a previous study indicating autosomal recessive inheritance for this ataxia, we performed whole-genome shotgun sequencing of a parent-offspring trio to identify amino acid-changing mutations consistent with this pattern. We used Sanger sequencing to exclude non-causal candidates. Together, our findings provide new insights into the onset and genetic complexity of ataxia, refining the value of the spastic Han-Wistar rat as a model for investigating mechanisms underlying hereditary ataxia and broader neurodegenerative disorders.

Hereditary ataxia↗
PubMed2026

Visualizing synaptic disruptions in the release and regulation of dopamine hotspots in Huntington's Disease.

Dopamine neuromodulation is a critical process that facilitates learning, motivation, and motor control. Disruption of these processes has been implicated in several neurodegenerative disorders including Huntington's Disease (HD). While dopaminergic signaling is a therapeutic target for treating physical and psychiatric HD symptoms, the mechanism by which dopaminergic dysfunction occurs during HD is unknown. New tools for the visualization of dopamine dynamics at the spatiotemporal resolution of neuromodulator release (ms) and dopaminergic boutons (µm) provide a richer understanding of how dopamine signaling is disrupted in HD. Here we employ near-infrared fluorescent catecholamine nanosensors (nIRCats) to image dopamine release within the striatum of R6/2 Huntington's Disease model mice of either sex. We find that dorsal striatal dopamine release decreases with progressive degeneration and that these deficits are primarily driven by a decrease in the number of nIRCat imaged dopamine release sites, termed dopamine hotspots, combined with decreased release fidelity. Using nIRCat's high spatial resolution, we track individual dopamine hotspots over repeated stimulations and pharmacological applications to measure dopamine release fidelity from individual sites. Compellingly, we found that D2-receptor (D2R) antagonist sulpiride drives increased fidelity of dopamine hotspot activity in wild type striatum but not in late-disease HD striatum, suggesting that D2R regulation of dopamine release is compromised in late HD. These findings, enabled by nIRCats, provide more detailed insights into how dopamine release is disrupted and dysregulated during Huntington's Disease.Significance statement Huntington's Disease (HD) is a neurodegenerative disorder with no cure. Dopamine signaling is known to deteriorate in HD but has not been studied at the level of individual release sites. Here, we image dopamine release from individual dopamine release sites in R6/2 HD mouse brain slices containing the striatum with novel dopamine nanosensors. We find that dopamine release site number and release fidelity are decreased in late HD. Furthermore, we demonstrate that D2-receptor signaling may be altered in late disease R6/2 HD mice, and that these disruptions are likely to drive decreased dopamine release fidelity over multiple stimulations. These findings suggest dopaminergic neurons projecting to the striatum as a potential therapeutic target for HD treatment to complement more commonly targeted medium spiny neurons.

Journal Article↗
PubMed2026

Comparison of Proteomic Analysis of Cerebrospinal Fluid From Neurological Patients With and Without Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by progressive muscle weakness in both bulbar and extremity muscles, leading to a diverse clinical phenotype with motor and non-motor symptoms. Approximately 85% of ALS cases are sporadic (sALS), while the remaining 10%-15% are familial (fALS). Biological biomarkers of sporadic ALS remain poorly understood, hindering precise patient screening, delaying diagnosis and negatively affecting prognosis. This study aims to identify potential proteomic biomarkers by comparing the cerebrospinal fluid (CSF) of sALS patients with that of patients suffering from other neurological diseases. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for proteomic profiling of CSF samples from 24 sALS patients and 26 patients with other neurological diseases. The complete protein expression profiles were compared using a two-tailed Student's t-test, with a p <&#x2009;0.05 considered statistically significant with additional FDR correction at the 0.1 level. Proteomic analysis of CSF samples identified significant quantitative changes in 96 proteins with threshold p&#x2009;<&#x2009;0.05 and 74 proteins with FDR <&#x2009;0.1 between sALS and non-ALS patients, including alterations in proteins associated with neurodegenerative processes, such as amyloid precursor proteins and inflammatory markers. CSF proteomic analysis reveals altered inflammatory and neurodegenerative metabolic pathways, providing valuable insights into the proteomic landscape of sALS. Several dysregulated proteins were consistent with the disease mechanisms highlighted in previous studies. These findings represent a step forward in developing personalised approaches for diagnosing and managing the disease.

Humans↗
PubMed2025

Ataxia and oculomotor apraxia caused by a large-scale deletion in the senataxin gene.

Senataxin, an RNA/DNA helicase, is a key protein providing genome stability and one of the best characterized R-loop-binding factors playing an important role in transcription and DNA repair processes. Pathogenic SETX gene variants cause autosomal recessive spinocerebellar ataxia with axonal neuropathy (AOA2, MIM #606002) and autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4, MIM #602433), rare neurodegenerative disorders characterized by juvenile onset of progressive cerebellar ataxia, axonal sensorimotor peripheral neuropathy, combined upper and lower motor neuron symptoms, and increased serum alpha-fetoprotein (AFP; specific for AOA2). We report two cases of adult patients presenting with cerebellar syndrome, scanned speech, and exercise intolerance which started in the second/third decade of life and were followed by muscle weakness and impaired gait coordination. Whole exome sequencing (WES) was performed to analyze single nucleotide and copy number variants. A decreased coverage of a genomic region of around 16&#xa0;kb on chromosome 9 (chr9:132,295,852-132,311,876), suggesting a deletion encompassing 5 exons of the SETX gene (exons 11-15, NM_015046.7) was observed. This homozygous SETX (9q34.13) deletion leads to a frame shift and consequently truncation of the helicase domain in the protein. Loss-of-function variants in the SETX gene are known to be pathogenic. Statistical analysis of NGS data from the Polish population identified a few heterozygous carriers, suggesting its region-specific origin.

Humans↗
PubMed2026

Applications of quantum AI in brain disorder diagnosis: A systematic review.

BACKGROUND AND OBJECTIVE: Brain disorder diagnosis and prediction remain challenging because neuroimaging, electrophysiological, behavioral, and multimodal data are high-dimensional, noisy, heterogeneous, and limited by small clinical cohorts. This systematic review synthesised applications of quantum artificial intelligence (QAI) for brain disorder diagnosis, prediction, detection, and monitoring. METHODS: Following PRISMA guidelines, studies published from 2016 to 13 January 2026 were retrieved from Scopus, Web of Science, and IEEE Xplore. After screening, 36 studies met the eligibility criteria and were qualitatively analysed according to disorder category, data modality, QAI method, implementation setting, validation strategy, and performance. RESULTS: At the broader disease-group level, neurodegenerative disorders were the most frequently investigated, followed by mental health and psychiatric disorders. At the individual level, Parkinson's disease and schizophrenia were the leading applications, followed by depression, anxiety, Alzheimer's disease, and stress-related tasks. MRI-based modalities were the most frequently used data source, followed by multimodal data and EEG. Methodologically, primary QAI approaches were dominated by quantum neural and QDL architectures, followed by quantum-inspired optimization or feature-selection methods and quantum-kernel/conventional QML classifiers. Qiskit/IBM Quantum and PennyLane were the most frequently reported quantum software frameworks. However, most studies relied on simulators, classical quantum-inspired implementations, or unclear implementation settings, with limited real-hardware evaluation. CONCLUSIONS: QAI shows emerging potential for brain disorder analysis, particularly through hybrid quantum-classical learning, quantum neural architectures, quantum-kernel methods, and quantum-inspired optimization. Nevertheless, current evidence remains preliminary and requires larger datasets, subject-level and external validation, fair classical benchmarking, noise-resilient circuits, real quantum hardware evaluation, explainability, and clinical validation.

Humans↗
PubMed2026

Recent medicinal chemistry efforts of targeting protein kinases for treating neurological conditions of Parkinson's and Alzheimer's diseases.

The human genome encodes a wide variety of protein kinases that regulate multiple cellular functions. These enzymes play a crucial role in amplifying and propagating intracellular signals during signal transduction. Dysregulation of protein kinase signaling is associated with vascular diseases, inflammatory disorders, cancer, and various neurological conditions. Kinase-targeted therapies have already demonstrated clinical efficacy in oncology and inflammatory diseases, prompting growing interest in their potential application in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Several kinases, including PDK1, CK1, CK2, c-Abl, p38 MAPK, PKA, GSK-3&#x3b2;, PINK1, and ROCK, have been implicated in the pathogenesis of AD and PD, highlighting their potential as therapeutic targets. However, the development of kinase inhibitors for central nervous system (CNS) disorders remains challenging due to limited blood-brain barrier (BBB) penetration and cytochrome P450-mediated metabolism. This review summarizes protein kinase targets involved in AD and PD, discusses kinase inhibitors under preclinical and clinical investigation, and highlights emerging strategies to overcome pharmacokinetic and therapeutic limitations in the development of disease-modifying therapies.

Journal Article↗
PubMed2026

Clinical and biochemical footprints of inherited disorders of autophagy.

Autophagy is an evolutionarily conserved lysosomal recycling system that integrates nutrient sensing, organelle quality control, proteostasis, cellular stress responses and metabolic adaptation. Autophagy is particularly relevant for post-mitotic tissue such as neurons, skin, and immune cells. Monogenic disorders disrupting autophagy or closely coupled endolysosomal trafficking pathways have recently emerged as a recognizable group of inherited metabolic diseases. These conditions are individually rare inborn errors of metabolism and collectively important because they bridge neurodevelopmental, neuromuscular and neurodegenerative disorders, including hereditary forms of Parkinson's disease, spastic paraplegias and neurodegeneration with brain iron accumulation. Multisystem involvement is common but variable. The prototypic disorder is EPG5-related Vici syndrome, in which defective autophagosome-lysosome fusion causes severe neurodevelopmental and multisystem disease. Other disorders may affect any step of the pathway, from phosphatidylinositol 3-phosphate effector biology and ATG conjugation/lipidation to autophagosome maturation, ATG9 trafficking, HOPS/CORVET-related vesicle trafficking (including VPS16 and VPS33A), autophagosome-lysosome fusion, autolysosome reformation and lysosome-mTOR signaling. Clinically, affected individuals commonly present with global developmental delay and/or intellectual disability, epilepsy, movement disorders including dystonia, parkinsonism, ataxia and spasticity, and both neuropathic and myopathic neuromuscular manifestations. A biphasic course with progressive neurodegeneration and variable multisystem (including ocular, cardiac, immunological, cutaneous and growth) involvement are important clinical clues. Diagnosis relies on careful phenotyping, brain MRI, targeted metabolic exclusion of mimics, genomic sequencing and functional assays in patient-derived cells as required. Supportive multidisciplinary management is essential. No disease-modifying therapy is currently established in humans, but pathway-based cellular assays, model systems and small-molecule or gene-replacement strategies are creating a rational therapeutic pipeline. Importantly, IEMbase dyadic nomenclature with system-level clinical annotations provides a standardized framework for quantifying shared phenotypic signatures across these ultra-rare conditions. This review summarizes pathobiochemistry, genetics, clinical presentation, diagnosis and treatment prospects for inherited disorders of autophagy.

Autophagosome↗
PubMed2025

Prediction and Evaluation of Protein Aggregation with Computational Methods.

Protein and peptide aggregation has recently become one of the most studied biomedical problems due to its central role in several neurodegenerative disorders and of biotechnological importance. Multiple in silico methods, databases, tools, and algorithms have been developed to predict aggregation of proteins and peptides to better understand fundamental mechanisms of various aggregation diseases. Here, we attempt to provide a brief overview of bioinformatic methods and tools to better understand molecular mechanisms of aggregation disorders. Furthermore, through a better understanding of protein aggregation mechanisms, it might be possible to design novel therapeutic agents to treat and hopefully prevent protein aggregation diseases.

Computational Biology↗