Treventis

Understanding the role of the peripheral immune system in neurodegenerative diseases is crucial, as it can both protect and inflame the brain, though the specific mechanisms remain unclear.

A study focusing on Alzheimer’s disease (AD) found large Aβ aggregates in the plasma of patients with MCI. These aggregates are associated with early AD-like brain pathology, as detected by PET imaging, and a decrease in CD18-rich monocytes. Their research identified complement receptor 4 (CR4) as a key binder of amyloids, with Aβ aggregates preferentially phagocytosed and stimulating lysosomal activity in stem cell-derived microglia through this receptor. Furthermore, activation of the KIM127 integrin in monocytes enhances size-selective phagocytosis of Aβ. Hydrodynamic calculations suggest that Aβ aggregates serve as an adhesion substrate for recruiting CD18-rich monocytes into the cortex.

These results emphasize the importance of CR4 in regulating amyloid homeostasis.

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https://www.nature.com/articles/s41467-024-45627-y

In a recent study using inducible endothelial cells (ECs), specific TAR DNA-binding protein 43 (TDP-43)–KO mice, scientists found that TDP-43 is crucial for driving angiogenesis, vascular barrier integrity, and blood vessel stability.

TDP-43, a key DNA/RNA-binding protein involved in gene regulation, is linked to several neurodegenerative diseases. Postnatal TDP-43 deletion in ECs caused retinal hypovascularization due to defective vessel growth, reduced EC proliferation, and migration. In mature blood vessels, TDP-43 loss disrupted the blood-brain barrier and led to vascular degeneration, accompanied by CNS inflammation and activation of microglia and astrocytes. Mechanistically, TDP-43 deletion disrupted the fibronectin matrix around growing vessels and reduced β-catenin signaling. These findings highlight TDP-43's essential role in developing and maintaining a stable, mature vascular system.

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-43

https://insight.jci.org/articles/view/177819

Microglial dysfunction is critical in Alzheimer's disease (AD) pathogenesis. A recent study explored a germline insertion/deletion variant in SIRPβ1, a receptor that aids amyloid-β (Aβ) phagocytosis via TYROBP.

Using the rs2209313 proxy in GERALD and GR@ACE series, as well as hippocampal samples from genotyped AD patients, the scientists found the variant alters SIRPβ1's isoform landscape, reducing Aβ binding and TYROBP affinity. Dup/Dup patients with MCI showed higher cerebrospinal fluid t-Tau/Aβ ratios and increased AD risk. MRIs showed worse initial AD response in Dup/Dup patients, with less hippocampal degeneration and fewer white matter hyperintensities, despite similar MMSE scores at diagnosis. The duplication correlates with higher TREM2 expression and increased microglial activation. The SIRPβ1 duplication impacts MCI-to-dementia conversion risk and AD progression, highlighting its potential as a modulator of the TREM2-TYROBP pathway.

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https://content.iospress.com/articles/journal-of-alzheimers-disease/jad231150

A new study demonstrated that dysregulation of synaptic homeostasis in entorhinal cortex layer II (ECII) neurons is crucial during the onset of AD tau pathology.

These neurons are the earliest to show tau protein aggregates and degeneration during prodromal Alzheimer’s disease (AD). Investigating the molecular mechanisms behind this vulnerability highlights important genes and pathways involved in the initial stages of AD. Through a data-driven functional genomics approach, the scientists modeled ECII neurons in silico and discovered the proto-oncogene DEK as a key regulator of tau pathology. Silencing DEK led to epigenetic changes that disrupted activity-induced transcription and neuronal excitability, resulting in tau accumulation in the somatodendritic compartment of ECII neurons. This is accompanied by microglia activation and neuron loss, which are hallmarks of early AD.

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https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awae051/7625227?login=false

In Alzheimer's disease (AD), the buildup of amyloid-beta (Aβ) plays a key role in forming neurotoxic aggregates.
While AD typically shows a decrease in overall brain activity, emerging research indicates that early on, Aβ may cause neurons to become overly active and even trigger seizure-like behaviors.

A recent study has uncovered that Aβ accumulation increases PSD-95 levels within laboratory-grown neurons and the brains of young APP/PS1 mice. This elevation in PSD-95 is traced back to a decrease in ubiquitination due to the Akt pathway's phosphorylation of the E3 ubiquitin ligase, Mdm2. Furthermore, an increase in PSD-95 facilitates the formation of excitatory synapses and enhances the activity of AMPA receptors on the neuron's surface, driven by Aβ. By targeting PSD-95 for inhibition, the scientists could mitigate these synaptic anomalies and decrease seizure-like activities in the APP/PS1 mice, pointing to a mechanism by which early Aβ pathology leads to neural hyperactivity.

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-95
https://www.embopress.org/doi/full/10.1038/s44319-024-00090-0

A C. elegans model was recently designed to investigate early Parkinson's disease (PD) stages, focusing on non-motor symptoms and neurodegeneration mechanisms without alpha-synuclein (Asyn) interference.

This model leverages the fact that C. elegans does not possess an Asyn homolog, offering a unique opportunity to study PD-related neurodegeneration. Utilizing RAC1/ced-10 mutants, corresponding to the human RAC1 gene crucial for dopaminergic neuron function and survival, they aimed to mimic early PD symptoms and lipid alterations seen in patients. Their findings reveal that these mutants display early developmental issues such as altered defecation cycles, GABAergic dysfunction, increased oxidative stress, and lipid metabolism changes, including elevated phosphatidylcholine and sphingomyelin levels.

These results mirror early PD's non-motor symptoms, neurotransmission defects, and metabolic shifts, establishing the C. elegans model as a valuable tool for early-stage PD research.

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https://www.sciencedirect.com/science/article/abs/pii/S030100822400008X?via%3Dihub

Parkinson’s disease is traditionally linked to motor symptoms and nigrostriatal degeneration but is now understood to involve multiple pathologies whose origins and roles in early stages remain unclear.

A recent study focused on individuals with mild motor deficits, identified without the severe criteria for Parkinson’s disease (PD) diagnosis, and not based on post-mortem Lewy pathology but clinical symptomology. Dividing the patients by the presence or absence of synucleinopathy, the scientists found that both groups exhibited similar losses in nigral dopaminergic neurons and putamenal innervation, alongside comparable degrees of phosphorylated tau pathology, not observed in controls.

This suggests that nigrostriatal neurodegeneration in early PD may occur independently of alpha-synuclein aggregation, potentially driven by tau pathology, challenging traditional views on the disease’s pathogenesis and highlighting the complexity of its early stages.

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https://academic.oup.com/brain/article/147/2/444/7450928?login=false

Brain region-specific degeneration and somatic expansions of the mutant Huntingtin (mHTT) CAG tract are key features of Huntington’s disease (HD).

However, the relationships among CAG expansions, death of specific cell types, and molecular events associated with these processes are not established. A new study using fluorescence-activated nuclear sorting (FANS) and deep molecular profiling was used to gain insight into the properties of human striatum and cerebellum cell types in HD donors. CAG expansions arise in mHTT tracts within the striatal medium spiny neurons (MSNs), cholinergic interneurons, cerebellar Purkinje neurons, and mutant ATXN3 in MSNs. CAG expansions in MSNs were also shown to be associated with higher levels of MSH2 and MSH3, inhibiting nucleolytic excision of CAG slip-outs by FAN1.

The study’s data supports a model in which CAG expansions are necessary but may not be sufficient for cell death.

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https://www.nature.com/articles/s41588-024-01653-6

A recent novel approach shows promise for therapeutic applications in the management of neurodegenerative diseases by blocking the interaction between the nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associating protein 1 (Keap1) within the cytosol elevating the body's antioxidant defenses.

Efforts to use peptides or small molecules for greater target specificity have been limited by their rapid degradation and poor cell membrane pe*******on. This study used protein-like polymers (PLPs) to overcome these limitations. The PLPs not only bind Keap1 with significantly higher affinity than individual peptides but also remain stable in serum, pe*****te cells efficiently, and specifically trigger the antioxidant response element pathway in cells, including primary cortical neurons.

This innovative approach indicates that Keap1/Nrf2-inhibitory PLPs could be a powerful tool in treating diseases marked by oxidative stress imbalance, including neurodegenerative diseases.

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https://onlinelibrary.wiley.com/doi/10.1002/adma.202311467

A new study introduced a ubiquitin-based mechanism essential for terminating the response to mitochondrial protein import stress.

The stress response pathways play a vital role in maintaining cellular and tissue stability by addressing harmful conditions; however, their extended activation leads to apoptosis and harms overall health. Central to this mechanism is the silencing factor of the integrated stress response (SIFI), an E3 ligase complex implicated in ataxia and dementia that is responsible for degrading both mitochondrial precursor proteins and components of the stress response. The SIFI complex uniquely identifies dual-purpose motifs within substrates that signal for both their localization and degradation, allowing it to stop stress responses post-crisis.

The ability to pharmacologically mute stress responses highlights the significance of ending these signals and suggests a potential strategy for treating neurodegenerative conditions linked to mitochondria dysfunction.

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https://www.nature.com/articles/s41586-023-06985-7

Amyloid proteins such as α-synuclein and tau, key players in Alzheimer’s and Parkinson’s diseases (PD), are known to assemble into fibrils with varying toxic effects, seeding capacities, and pathologies, highlighting the importance of understanding these processes for novel diagnostics and treatments.

A new study found that modifying α-synuclein monomers with O-GlcNAc leads to unique amyloid fibrils, identified by cryogenic electron microscopy, demonstrating reduced seeding efficiency in PD models. The interaction between these modified fibrils and heat shock proteins was shown to be critical in diminishing their pathological seeding, revealing a pivotal role of O-GlcNAc modification in altering fibril interactions and reducing their disease-promoting activities. These insights emphasize the significance of posttranslational modifications in guiding the characteristics and disease relevance of amyloid fibrils.

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https://www.nature.com/articles/s41589-024-01551-2

Extrasynaptic NMDA receptors (eNMDARs) have been identified as key drivers of amyotrophic lateral sclerosis (ALS) progression, via a toxic signaling mechanism.

The novel therapeutic approach involves using the TwinF interface (TI) inhibitor, FP802, which uniquely targets and disrupts the harmful NMDAR/TRPM4 signaling complex without affecting the essential functions of synaptic NMDARs. This strategy has shown promising results in the SOD1G93A ALS mouse model, where FP802 administration post-disease onset stopped motor neuron loss, improved motor functions, and extended lifespan by reducing the levels of the neurofilament light chain, a serum biomarker for ALS. Additionally, FP802 demonstrated protective effects against NMDA-induced neuronal death in brain organoids derived from ALS patient iPSCs, emphasizing its therapeutic potential. FP802 may offer a potential new avenue for SOD1-implicated ALS treatment, focusing on mitigating eNMDAR-mediated neuronal toxicity.

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https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(24)00036-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2666379124000363%3Fshowall%3Dtrue

While VAPB (Vesicle-associated membrane protein)-associated proteins B and C have been investigated in the context of ALS and other neurodegenerative conditions, their roles in oncology, particularly in cancer, remain underexplored.

In a recent medulloblastoma study, VAPB's potential connection to cancer progression was recently extensively studied. The research indicated a strong association between high VAPB expression in medulloblastoma cases and reduced patient survival rates, highlighting its influence on the aggressive nature of the disease. Experiments demonstrated that medulloblastoma cell growth relies on VAPB, with both in vitro and in vivo models demonstrating a slowed proliferation upon VAPB deletion. This effect is accompanied by a decreased expression of proteins within the WNT signaling pathway. These insights suggest that targeting VAPB could offer new avenues for medulloblastoma therapy, making it a potentially viable candidate for therapeutic intervention.

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https://www.nature.com/articles/s41598-023-45319-5

Carrying the APOE ε4 allele significantly raises the risk of developing Alzheimer's disease (AD) by impacting autophagy, a critical process for cellular health, and is strongly linked to a higher accumulation of amyloid plaques.

Recent research efforts have identified that the ApoE4 protein inhibits the transcription of key autophagy genes by binding to a regulatory element in their promoters. A sophisticated research strategy led to the discovery of small molecules capable of preventing ApoE4's harmful interaction with DNA; these findings were confirmed through experiments in both cell cultures and ApoE4-specific mice animal models. Notably, one of these molecules was shown to effectively mitigate amyloid-like buildup in a C. elegans model of AD. This advancement emphasizes the potential for pharmacologically targeting ApoE4's interference with autophagy as a novel therapeutic approach, offering hope for new treatment approaches that address the underlying genetic factors of AD.

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https://www.nature.com/articles/s42003-024-05767-9

A novel study utilizing modern sequencing techniques, including single-cell sequencing for chromatin accessibility and RNA sequencing, has provided new insights into the peripheral immune system's role in Alzheimer's disease (AD).

This research uncovered significant findings, such as an abundance of open chromatin within AD peripheral immune cells, pointing towards an active epigenetic environment. CD8 T cells were found to display chromatin modifications linked to the expression of the CXCR3 gene promoter, while monocytes exhibited chromatin alterations dependent on APOE genotype. Additionally, this study identified chromatin modifications near genes implicated in sporadic AD, suggesting a deeper epigenetic influence on AD's genetic risk factors. Additionally, monocytes revealed a unique chromatin environment conducive to the binding of the RELA transcription factor. These findings reveal the complex interplay between AD's genetic and epigenetic landscapes.

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https://www.cell.com/neuron/abstract/S0896-6273(24)00039-4

Age and the APOE4 gene variants are key and significant risk factors for Alzheimer's disease (AD), influencing the emergence of a unique microglial cell population known as terminally inflammatory microglia (TIM), which co-express stress and inflammatory markers and show impaired cellular function.

Present in both AD model mice and human patients, TIM are associated with amyloid-beta plaques and exhibits a reduced ability to clear these plaques. The scientist's comprehensive study integrated single-cell and spatial transcriptomics, revealing that TIM frequency increases with age and APOE4 presence, indicating an exhausted-like state in AD's neuroimmune landscape. Interestingly, aducanumab, an anti-amyloid treatment, modulates TIM characteristics in an APOE-dependent manner, highlighting TIM's potential as a therapeutic target in AD, especially among APOE4 carriers and older individuals.

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https://www.cell.com/immunity/abstract/S1074-7613(23)00532-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1074761323005320%3Fshowall%3Dtrue

Phosphorylation of α-synuclein at serine-129 (α-syn Ser129P) marks a key pathological feature in synucleinopathies; however, its physiological role is less understood.

A recent study reveals that α-syn Ser129P occurs in specific regions of the brain, suggesting tight regulation. Contrary to its known pathologic roles, scientists discovered that blocking α-syn Ser129P hinders α-syn's ability to modulate synaptic activity, indicating its essential function in normal synaptic operations. Neuronal activity increases α-syn Ser129P, which facilitates crucial protein-protein interactions at synapses. Using AlphaFold2 modeling and membrane-binding simulations, the scientists propose that Ser129P induces structural changes, enhancing α-syn's interaction with synaptic proteins. This insight shifts the paradigm of α-syn Ser129P from merely a pathological hallmark to a functional player in synapse modulation, offering a novel perspective for drug development targeting synucleinopathies.

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https://www.cell.com/neuron/fulltext/S0896-6273(23)00894-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627323008942%3Fshowall%3Dtrue

Developing diagnostics and therapies for synucleinopathies such as Parkinson's disease is complicated by the absence of disease-modifying drugs.

Recent work introduced digital seed amplification assays (SAAs) for precisely detecting and quantifying α-synuclein (AS) aggregates, critical for diagnosing, assessing disease severity, and monitoring treatment effects. Scientists developed these assays by partitioning reactions into microcompartments and employing immunocapture techniques, enabling the identification of AS aggregates in patient samples, including brain tissue and cerebrospinal fluid, using pre-formed fibrils as seeds, that capture aggregates with antibody-coated magnetic beads. Furthermore, they quantified the impact of small-molecule inhibitors on AS aggregation, showcasing the assays' potential in evaluating new therapeutics offering significant prospects for understanding, neurodegenerative diseases characterized by AS aggregation.

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#α-synuclein




https://www.pnas.org/doi/10.1073/pnas.2312031121

Alzheimer's disease involves the accumulation of amyloid-beta (Aβ) and tau proteins, impacting neuronal activity and function.

Current research has explored their separate and combined effects on brain function using a whole-brain dynamic model in order to adjust the excitation-inhibition balance. The scientists discovered Aβ's significant influence during the mild cognitive impairment early stage, whereas tau's impact becomes predominant in Alzheimer's disease's later stages. This study emphasizes the pivotal roles of Aβ and tau in neuronal dynamics, using regional distributions to model large-scale brain functions in Alzheimer's patients.

The scientists' findings help to build on the current understanding of these proteins' interaction, paving the way for future research on biomarkers as well as potential therapeutic targets using in-silico methods.

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https://alzres.biomedcentral.com/articles/10.1186/s13195-023-01349-9

SynapShot, a novel method using dimerization-dependent fluorescent proteins (ddFPs) alongside engineered synaptic adhesion molecules, offers a breakthrough in visualizing the dynamic structure of synapses.

Traditional techniques fail to capture the reversible and bidirectional shifts in synaptic contacts during physiological activities; however, SynapShot overcomes these limitations, enabling the real-time observation of synaptic adjustments. Employing both green and red ddFPs allows for simultaneous tracking of two distinct synaptic populations. Importantly, its red-shifted version is compatible with blue light optogenetic methods, facilitating the study of synaptic behavior while manipulating specific neural pathways.

SynapShot's capability allows for the visualization of structural synaptic modifications within the mouse brain across a spectrum of behaviors, marking a significant advancement in understanding synaptic plasticity and brain function regulation.

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https://www.nature.com/articles/s41592-023-02122-4

Alzheimer's disease (AD) involves complex neurodegenerative processes, with Death Induced by Survival Gene Elimination (DISE) emerging as a vital mechanism of cell death.

DISE operates through short(s) RNAs that use the RNA-induced silencing complex (RISC) for RNA interference, targeting genes essential for survival via specific G-rich 6mer seed sequences. Current research employing Argonaute precipitation and RNA sequencing (Ago-RP-Seq) reveals that in AD models, aging brains, neurons derived from AD patients, and cells treated with Aβ42 oligomers, there is an increase in toxic 6mer seed sequences within RISC-bound sRNAs. Conversely, the brains of "SuperAgers" exhibit a predominance of nontoxic 6mer seeds.

This study demonstrates that depletion of nontoxic sRNAs increases sensitivity to Aβ42-induced cell death, while reintroduction offers protection, suggesting that enhancing nontoxic miRNAs or inhibiting toxic sRNAs could provide avenues to mitigate AD-related neurodegeneration.

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https://www.nature.com/articles/s41467-023-44465-8

Molecules prone to aggregation are known to form fibrillar deposits and proteopathic seeds, promoting the misfolding of tau proteins.

The connection between these seeds and the fibrils associated with tau-related diseases remains unclear. A recent study using mass spectrometry and bioassays analyzed both the PBS extractable and sarkosyl insoluble fibrillar tau species from human Alzheimer's brain samples, identifying post-translational modifications (PTMs) such as phosphorylation, acetylation, and ubiquitination. These distinctions between the PBS-extracted seeds and sarkosyl-insoluble tau demonstrated variations in PTM abundance and revealed the presence of specific PTMs. The ubiquitin presence and other PTMs in PBS-extracted tau correlated with tau quantity in seed fractions, bioactivity, and disease severity.

Their findings suggest that PTMs on bioactive, seed-competent PBS tau differ from those on mature fibrils, implying these seeds are an early form of fibril-forming tau species.

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https://academic.oup.com/brain/article-abstract/147/2/637/7471794?redirectedFrom=fulltext&login=false

A recent study demonstrated that the commercially available p-tau217 blood test accurately identifies Alzheimer's disease (AD) pathology, mirroring the precision of cerebrospinal fluid (CSF) biomarkers for amyloid β (Aβ) and tau abnormalities.

The study confirmed the test's effectiveness in detecting Aβ and tau pathologies, with findings comparable to CSF biomarkers, utilizing data from three cohorts. A consistent three-tier reference for Aβ pathology reduced further testing needs by 80%, highlighting the test's efficiency. Notably, p-tau217 levels increased annually in individuals positive for Aβ, especially those with concurrent tau positivity. This research reveals the potential of the commercially available p-tau217 blood test as a valuable tool for early AD diagnosis and monitoring, offering a practical alternative to traditional methods with reproducible results across different study groups as well as its ability to detect longitudinal changes that include AD preclinical stages.

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https://jamanetwork.com/journals/jamaneurology/fullarticle/2813751

In the majority of amyotrophic lateral sclerosis (ALS) cases and approximately half of all frontotemporal dementia (FTD) cases, the mislocalization of TDP-43 from the nucleus to the cytoplasm is linked to the inclusion of hidden exons in mRNA, leading to the creation of new proteins.

A recent study using neurons derived from iPSCs that lack TDP-43 revealed that its absence causes incorrect splicing and the formation of new proteins, similar to those found in ALS and FTD patients' cerebrospinal fluid (CSF). This environment degrades transcripts, affecting cell functions, and generates unusual peptides that may interfere with protein interactions, potentially playing a role in the diseases' pathological progression. The discovery of 65 peptides from hidden exons in these neurons reflects the observations in the patient's brain tissue, and CSF highlights TDP-43's vital role in ALS and FTD etiology.

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https://www.science.org/doi/10.1126/scitranslmed.adg7162

Protein misfolding leads to the formation of toxic intermediates, driving the etiologies of severe neurodegenerative diseases such as Alzheimer's disease (AD).

The amyloid-β (Aβ) fibrils associated with AD are believed to catalyze their replication. A recent study identified a specific Aβ42 fibril region as a vital site for catalyzation. Molecular chaperones, such as the BRICHOS domain of the Bri2 protein, have been found to disrupt this harmful cycle by attaching to the amyloid fibrils. A specific site on the Aβ42 fibril has been recognized by a modified Bri2 BRICHOS variant. This interaction effectively stops the fibril from catalyzing further toxic entities, revealing a critical site of aggregation. This interaction suggests a mechanism by which molecular chaperones can block the progression of toxic nucleation, offering insights into how targeted interventions could mitigate the effects of diseases caused by protein misfolding.

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https://www.nature.com/articles/s41467-024-45192-4

RNA metabolism, including gene and transposable element (TE) regulation. Its chronic deficiency not only impedes cell proliferation and DNA damage response but also disrupts gene expression.

This disruption stems from reduced R-loops and 5-hydroxymethylcytosine (5hmC) in certain genes and enhancers, leading to decreased expression of crucial genes and their distal targets. Moreover, TDP-43 deficiency causes an unwanted increase of R-loops and 5hmC in TEs, triggering inappropriate activation. These molecular changes suggest TDP-43's vital role in maintaining R-loop-5hmC balance across gene bodies, enhancers, and TEs. Their research demonstrates how TDP-43's modulation of this balance contributes broadly to the pathogenesis of neurodegenerative diseases through altered gene regulation and TE activity, underlining its extensive genomic impact and potential link to neurodegenerative disorder etiologies.

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https://www.cell.com/cell-reports/fulltext/S2211-1247(23)01673-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS221112472301673X%3Fshowall%3Dtrue

Alzheimer's disease (AD) exhibits profound molecular diversity, emphasizing the importance of personalized medicine.

Utilizing cerebrospinal fluid proteomics, researchers discerned AD subtypes among 419 patients, differentiated by protein changes linked to specific processes: neuronal hyperplasticity (subtype 1), immune response (subtype 2), RNA regulation (subtype 3), choroid plexus issues (subtype 4), and blood-brain barrier integrity (subtype 5). These subtypes align with unique genetic risk factors, like TREM2 R47H in subtype 1, and vary in clinical progression as well as brain atrophy. This molecular heterogeneity highlights the need for targeted AD therapies, moving beyond a one-size-fits-all approach. Identifying subtypes through proteomic profiles suggests a path toward precision medicine, tailoring treatments to individual molecular characteristics and potentially improving patient outcomes and quality of life in AD management.

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https://www.nature.com/articles/s43587-023-00550-7