TDP-43 as a potential retinal biomarker for neurodegenerative diseases

Frontiers in Neuroscience, Год журнала: 2025, Номер 19

Опубликована: Фев. 12, 2025

TDP-43 proteinopathies are a spectrum of neurodegenerative diseases (NDDs) characterized by the pathological cytoplasmic aggregation protein. These include amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer’s disease (AD), chronic traumatic encephalopathy (CTE), and others. in eye shows promise as biomarker for these NDDs. Several studies have identified inclusions retinal layers donors with ALS, FTLD, AD, CTE, other conditions using immunohistochemistry. Our findings suggest that aggregates human retina most prevalent FTLD-TDP, suggesting may provide reliable context studying potential biomarker. Animal model been pivotal exploring TDP-43’s roles retina, including its nuclear localization, RNA binding properties, interactions proteins. Despite advances, more research is needed to develop therapeutic strategies. A major limitation autopsy lack corresponding brain pathology assessments confirm proteinopathy diagnosis staging. Other limitations small sample sizes, antemortem clinical histories, limited comparisons across multiple Future directions NDDs tracers, hyperspectral imaging, oculomics, machine learning development.

Язык: Английский

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Mitigating a TDP-43 proteinopathy by targeting ataxin-2 using RNA-targeting CRISPR effector proteins

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Окт. 14, 2023

The TDP-43 proteinopathies, which include amyotrophic lateral sclerosis and frontotemporal dementia, are a devastating group of neurodegenerative disorders that characterized by the mislocalization aggregation TDP-43. Here we demonstrate RNA-targeting CRISPR effector proteins, programmable class gene silencing agents includes Cas13 family enzymes Cas7-11, can be used to mitigate pathology when programmed target ataxin-2, modifier TDP-43-associated toxicity. In addition inhibiting transit stress granules, find in vivo delivery an ataxin-2-targeting system mouse model proteinopathy improved functional deficits, extended survival, reduced severity neuropathological hallmarks. Further, benchmark platforms against ataxin-2 high-fidelity forms possess transcriptome-wide specificity compared Cas7-11 first-generation effector. Our results potential technology for proteinopathies.

Язык: Английский

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Elevated nuclear TDP-43 induces constitutive exon skipping

Molecular Neurodegeneration, Год журнала: 2024, Номер 19(1)

Опубликована: Июнь 9, 2024

Cytoplasmic inclusions and loss of nuclear TDP-43 are key pathological features found in several neurodegenerative disorders, suggesting both gain- loss-of-function mechanisms disease. To study gain-of-function, overexpression has been used to generate vitro vivo model systems.

Язык: Английский

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Alzheimer’s Disease: Exploring the Landscape of Cognitive Decline

ACS Chemical Neuroscience, Год журнала: 2024, Номер 15(21), С. 3800 - 3827

Опубликована: Окт. 11, 2024

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. The pathology of AD marked the accumulation amyloid beta plaques tau protein tangles in brain, along with neuroinflammation synaptic dysfunction. Genetic factors, such as mutations APP, PSEN1, PSEN2 genes, well APOE ε4 allele, contribute to increased risk acquiring AD. Currently available treatments provide symptomatic relief but do not halt progression. Research efforts are focused on developing disease-modifying therapies that target underlying pathological mechanisms Advances identification validation reliable biomarkers for hold great promise enhancing early diagnosis, monitoring progression, assessing treatment response clinical practice effort alleviate burden this devastating disease. In paper, we analyze data from CAS Content Collection summarize research progress We examine publication landscape insights into current knowledge advances developments. also review most discussed emerging concepts assess strategies combat explore genetic pharmacological targets, comorbid diseases. Finally, inspect applications products against their development pipelines drug repurposing. objective broad overview evolving regarding AD, outline challenges, evaluate growth opportunities further combating

Язык: Английский

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Optical Control over Liquid–Liquid Phase Separation

Small Methods, Год журнала: 2024, Номер unknown

Опубликована: Март 26, 2024

Abstract Liquid–liquid phase separation (LLPS) is responsible for the emergence of intracellular membrane‐less organelles and development coacervate protocells. Benefitting from advantages simplicity, precision, programmability, noninvasiveness, light has become an effective tool to regulate assembly dynamics LLPS, mediate various biochemical processes associated with LLPS. In this review, recent advances in optically controlling within living organisms are summarized, thereby modulating a series biological including irreversible protein aggregation pathologies, transcription activation, metabolic flux, genomic rearrangements, enzymatic reactions. Among these, systems (i.e., optoDroplet, Corelet, PixELL, CasDrop, other optogenetic systems) that enable photo‐mediated control over biomolecular condensation highlighted. The design photoactive complex protocells laboratory settings by utilizing photochromic molecules such as azobenzene diarylethene further discussed. This review expected provide in‐depth insights into separation‐associated processes, bio‐metabolism, diseases.

Язык: Английский

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RNA and condensates: Disease implications and therapeutic opportunities

Cell chemical biology, Год журнала: 2024, Номер 31(9), С. 1593 - 1609

Опубликована: Сен. 1, 2024

Язык: Английский

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Unveiling Acid-Sensing Ion Channels (ASICs) in Neurodegeneration: Implications for Disease Pathogenesis and Therapeutic Strategies

Current Pharmacology Reports, Год журнала: 2025, Номер 11(1)

Опубликована: Март 11, 2025

Язык: Английский

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TDP-43 Proteinopathy Specific Biomarker Development

Cells, Год журнала: 2023, Номер 12(4), С. 597 - 597

Опубликована: Фев. 12, 2023

TDP-43 is the primary or secondary pathological hallmark of neurodegenerative diseases, such as amyotrophic lateral sclerosis, half frontotemporal dementia cases, and limbic age-related encephalopathy, which clinically resembles Alzheimer’s dementia. In a biomarker that can detect proteinopathy in life would help to stratify patients according their definite diagnosis pathology, rather than clinical subgroups uncertain pathology. For therapies developed target proteins cause disease track underlying pathology greatly enhance undertakings. This article reviews latest developments outlooks deriving TDP-43-specific biomarkers from pathophysiological processes involved development studies using biosamples entities associated with investigate candidates.

Язык: Английский

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Involvement of CB1 and CB2 receptors in neuroprotective effects of cannabinoids in experimental TDP-43 related frontotemporal dementia using male mice

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 174, С. 116473 - 116473

Опубликована: Март 24, 2024

The elevation of endocannabinoid levels through inhibiting their degradation afforded neuroprotection in CaMKIIα-TDP-43 mice, a conditional transgenic model frontotemporal dementia. However, which cannabinoid receptors are mediating these benefits is still pending to be elucidated. We have investigated the involvement CB1 and CB2 receptor using chronic treatments with selective ligands analysis cognitive deterioration Novel Object Recognition test, immunostaining for neuronal glial markers two areas interest Our results confirmed therapeutic value activating either or receptor, improvements animal performance preservation pyramidal neurons, particular medial prefrontal cortex, attenuation reactivity, hippocampus. In addition, activation both reduced elevated TDP-43 cortex an effect exerted by mechanisms that currently under investigation. These data reinforce notion may represent promising therapy against TDP-43-induced neuropathology Future studies will confirm benefits, one agonists used here, has been thoroughly characterized clinical development.

Язык: Английский

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Mitigation of TDP-43 toxic phenotype by an RGNEF fragment in amyotrophic lateral sclerosis models

Brain, Год журнала: 2024, Номер 147(6), С. 2053 - 2068

Опубликована: Май 13, 2024

Abstract Aggregation of the RNA-binding protein TAR DNA binding (TDP-43) is a hallmark TDP-proteinopathies including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As TDP-43 aggregation dysregulation are causative neuronal death, there special interest in targeting this as therapeutic approach. Previously, we found that extensively co-aggregated with dual function GEF (guanine exchange factor) rho guanine nucleotide factor (RGNEF) ALS patients. Here, show an N-terminal fragment RGNEF (NF242) interacts directly RNA recognition motifs competing IPT/TIG domain NF242 essential for interaction. Genetic expression fruit fly model overexpressing suppressed neuropathological phenotype increasing lifespan, abolishing motor defects preventing neurodegeneration. Intracerebroventricular injections AAV9/NF242 severe murine (rNLS8) improved lifespan phenotype, decreased neuroinflammation markers. Our results demonstrate innovative way to target proteinopathies using strong affinity aggregates mechanism includes competition sequestration, suggesting promising strategy such FTD.

Язык: Английский

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