Search Results (158)

Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and Huntington’s disease represent a major challenge in neuroscience due to their complex, multifactorial nature and the absence of curative treatments. These disorders share common molecular mechanisms, including oxidative stress, mitochondrial dysfunction, proteostasis collapse, calcium dyshomeostasis, chronic neuroinflammation, and the prion-like propagation of misfolded proteins. Together, these processes trigger a cascade of cellular damage that culminates in synaptic dysfunction and programmed neuronal death. This review integrates current evidence on the sequential stages of neurodegeneration, emphasizing the convergence of oxidative, inflammatory, and proteotoxic pathways that drive neuronal vulnerability. Moreover, it explores emerging therapeutic strategies aimed at restoring cellular homeostasis, such as Nrf2 activation, modulation of the unfolded protein response (UPR), enhancement of autophagy, immunotherapy against pathological proteins, and gene therapy approaches. The dynamic interplay among mitochondria, endoplasmic reticulum, and glial cells is highlighted as a central element in disease progression. Understanding these interconnected mechanisms provides a foundation for developing multi-targeted interventions capable of halting or delaying neuronal loss and improving clinical outcomes in neurodegenerative disorders. This work provides an integrative and introductory overview of the convergent mechanisms underlying neurodegeneration rather than an exhaustive mechanistic analysis. Full article

Creutzfeldt–Jakob disease (CJD) is a rare but devastating neurodegenerative disorder characterized by the pathological misfolding of the cellular prion protein (PrP^C) into the pathogenic isoform-scrapie prion protein (PrP^Sc), ultimately leading to fatal outcomes. Cerebrospinal fluid (CSF) biomarkers play a pivotal role in early diagnosis, longitudinal monitoring, and prognostic assessment, thereby enhancing the clinical management of this challenging disease. This review summarizes the established CSF biomarkers, 14-3-3 protein, tau protein (total tau), phosphorylated tau isoforms, α-synuclein, neurofilament light chain (Nfl), S100B, neuron-specific enolase (NSE), and phosphorylated neurofilament heavy chain (pNFH), highlighting typical sensitivity ranges (14-3-3 ~70–85%; RT-QuIC > 90%) and subtype-dependent performance variation. We further dissect limitations related to assay variability, inter-laboratory cut-off inconsistencies, and reduced specificity in non-prion dementias. Looking ahead, we discuss emerging multi-omics discovery, integration of CSF with blood-based biomarkers and imaging signatures, and AI-enabled diagnostic modeling. We propose a three-tier biomarker framework combining Real-Time Quaking-Induced Conversion (RT-QuIC) as a confirmatory assay, tau/NfL/pNFH as injury-severity indicators, and multi-omics-derived signatures for early detection and prognosis stratification. Full article

The cellular prion protein (PrP^C) displays a functional repertoire that extends well beyond its classical link to transmissible spongiform encephalopathies. Abundant in the nervous system and localized within lipid raft microdomains, PrP^C has emerged as a multifunctional signaling platform that regulates cell differentiation, neurogenesis, neuroprotection, and synaptic plasticity. Recent evidence highlights its dynamic expression in stem cell populations, where it participates in multimolecular complexes that control lineage commitment, particularly during neuronal differentiation. PrP^C expression tightly correlates with stem cell status, making it a promising biomarker of stemness and developmental progression. Through interactions with growth factors, extracellular matrix components, and synaptic proteins, PrP^C functions as a molecular integrator of signals essential for tissue repair and regeneration. Preclinical studies demonstrate that recombinant PrP^C can stimulate neurogenesis and tissue repair, while monoclonal antibodies modulate its physiological and pathological functions. Likewise, cell-based therapies leveraging PrP^C-enriched stem cells or PrP^C-dependent signaling profiles have shown promise in models of neurodegeneration and ischemia. Conversely, dysregulated PrP^C expression has also been observed in solid tumors, where it contributes to cancer cell survival, proliferation, metastasis, and therapy resistance, reinforcing its role as a regulator of cell fate and an oncological target. This review integrates stem cell biology, tissue regeneration, and oncology into a unified framework, offering a novel perspective in which PrP^C emerges as a shared molecular hub governing both physiological repair and pathological tumor behavior, opening previously unrecognized conceptual and translational opportunities. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and the presence of intracellular α-synuclein (αSyn) aggregates known as Lewy bodies (LB). αSyn, a presynaptic protein, is believed to play a crucial role in synaptic function, neurotransmitter release, and neuronal plasticity. However, its misfolding and aggregation are thought to be central to PD pathogenesis. This review provides a comprehensive analysis of αSyn’s role in PD, exploring its normal physiological functions, pathological mechanisms, and therapeutic potential. The pathological transformation of αSyn involves structural alterations that promote oligomerization and fibrillization, leading to toxic gain-of-function effects. These aggregates disrupt cellular homeostasis through mechanisms including mitochondrial dysfunction, oxidative stress, lysosomal impairment, and endoplasmic reticulum stress. Furthermore, pathogenic αSyn is thought to exacerbate neurodegeneration via prion-like spread along interconnected neuronal circuits. Emerging evidence highlights the frequent co-occurrence of other proteinopathies, such as tau and amyloid-β, which may synergistically accelerate disease progression. Targeting αSyn has emerged as a potential therapeutic strategy. Approaches such as immunotherapy, small-molecule inhibitors, gene silencing, and modulation of protein degradation pathways (e.g., autophagy and proteasomal systems) are actively being explored. Additionally, lifestyle-based interventions, particularly exercise, have shown neuroprotective effects, potentially mediated by irisin—a myokine implicated in protein clearance and synaptic resilience—underscoring the importance of multimodal strategies in PD management. Full article

Low-complexity domains (LCDs) are protein regions characterized by a simple amino acid composition and low sequence complexity, as they are typically composed of repeats or a limited set of a few amino acids. Historically dismissed as “garbage sequences”, these regions are now acknowledged as critical functional elements. This review systematically explores the structural characteristics, biological functions, pathological roles, and research methodologies associated with LCDs. Structurally, LCDs are marked by intrinsic disorder and conformational dynamics, with their amino acid composition (e.g., G/Y-rich, Q-rich, S/R-rich, P-rich) dictating structural tendencies (e.g., β-sheet formation, phase separation ability). Functionally, LCDs mediate protein–protein interactions, drive liquid–liquid phase separation (LLPS) to form biomolecular condensates, and play roles in signal transduction, transcriptional regulation, cytoskeletal organization, and nuclear pore transportation. Pathologically, LCD dysfunction—such as aberrant phase separation or aggregation—is implicated in neurodegenerative diseases (e.g., ALS, AD), cancer (e.g., Ewing sarcoma), and prion diseases. We also summarize the methodological advances in LCD research, including biochemical (CD, NMR), structural (cryo-EM, HDX-MS), cellular (fluorescence microscopy), and computational (MD simulations, AI prediction) approaches. Finally, we highlight current challenges (e.g., structural heterogeneity, causal ambiguity of phase separation) and future directions (e.g., single-molecule techniques, AI-driven LCD design, targeted therapies). This review provides a comprehensive perspective on LCDs, illuminating their pivotal roles in cellular physiology and disease, and offering insights for future research and therapeutic development. Full article

Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease are characterized by progressive neuronal loss, driven mainly by the misfolding, aggregation, and accumulation of each disease’s specific proteins. These pathogenic aggregates, including tau, α-synuclein, TDP-43, and huntingtin, disrupt cellular proteostasis and initiate cascades of neuroinflammation, oxidative stress, mitochondrial dysfunction, and synaptic failure. While protein aggregation has been a long-recognized hallmark of these disorders, growing evidence points towards a more complex interplay of initial molecular pathways with defects in RNA processing, stress granule pathology, and cell-type-specific vulnerability. Notably, such events may manifest differentially with respect to sex and are further modulated by age-related loss of the protein quality control processes like the ubiquitin–proteasome pathway, autophagy–lysosome pathway, and molecular chaperones. This review synthesizes current insights into the structural and functional dynamics of protein aggregation and its significance for neuronal well-being. It highlights the role of post-translational modifications, prion-like transmission, and aggregation kinetics in the regulation of toxicity. The review further discusses promising therapeutic strategies centered on restoring proteostasis, including small molecules that inhibit aggregation, protein clearance pathway enhancers, immunotherapy, antioxidant therapy, and diagnostic prospects such as the identification of reliable molecular signatures in bodily fluids that can reflect pathological changes even before clinical symptoms emerge. Advancements in single-cell transcriptomics and multi-omics platforms, which are changing our understanding of disease onset and progression and opening avenues for precision medicine and personalized treatments, were also discussed. Ultimately, deciphering the molecular logic that distinguishes physiological from pathological protein assemblies and understanding how cellular systems fail to adapt under stress will be key to the development of effective, disease-modifying therapies for these debilitating disorders. Full article

Background/Objectives: The voltage-gated potassium channels of the Kv4 family (Kv4.1, Kv4.2, Kv4.3) regulate neuronal excitability and synaptic integration. The dysregulation of these channels has been linked to neurodegenerative diseases, such as Alzheimer’s disease (AD), spinocerebellar ataxias, amyotrophic lateral sclerosis (ALS), prion diseases, and Parkinson’s disease (PD). Current evidence is scattered across diverse models, and a systematic synthesis is lacking. This review seeks to compile and analyze data on Kv4 channel alterations in neurodegeneration, focusing on genetic variants, functional changes, and phenotypic consequences. Methods: A systematic search was conducted for peer-reviewed studies, including human participants, human-derived cell models, and relevant animal models. Studies were considered eligible if they investigated Kv4.1–Kv4.3 (encoded by gene encoding the Kv4.1-Kv4.3 α-subunit of voltage-gated A-type potassium channels (KCND1-KCND3)) expression, function, or genetic variants, as well as associated auxiliary subunits such as DPP6 (dipeptidyl peptidase–like protein 6) and KChIP2 (Kv channel–interacting protein 2), in neurodegenerative diseases. Both observational and experimental designs were considered. Data extraction included disease type, model, Kv4 subunit, functional or genetic findings, and key outcomes. Risk of bias was assessed in all included studies. Results: Kv4 channels exhibit significant functional and expression changes in various neurodegenerative diseases. In AD and prionopathies, reduced Kv4.1- and Kv4.2-mediated currents contribute to neuronal hyperexcitability. In spinocerebellar ataxias, KCND3 mutations cause loss- or gain-of-function phenotypes in Kv4.3, disrupting cerebellar signaling. In models of ALS and PD, Kv4 dysfunction correlates with altered neuronal excitability and can be modulated pharmacologically. Subunit modulators such as DPP6 and KChIP2 influence channel function and could represent therapeutic targets. Conclusions: Kv4 channels are crucial for neuronal excitability in multiple neurodegenerative contexts. Dysregulation through genetic or pathological mechanisms contributes to functional deficits, highlighting Kv4 channels as promising targets for interventions aimed at restoring electrical homeostasis and mitigating early neuronal dysfunction. Full article

Seed amplification assays (SAA) targeting misfolded α-synuclein have emerged as powerful tools for the diagnosis and study of synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies, and multipßle system atrophy. These assays exploit the prion-like seeding properties of pathological α-synuclein to detect minute amounts of misfolded protein in biological specimens. the PubMed database was searched according to our study criteria, and 55 clinical studies comprised the final literature review. the majority of studies have focused on patients at various stages of PD, with cerebrospinal fluid (CSF) being the most commonly investigated biological specimen. Diagnostic utility was most pronounced in the CSF of PD patients, whereas results from other biological samples and across different synucleinopathies have been more modest. α-syn SAA demonstrate significant diagnostic potential in synucleinopathies. Additional applications may include monitoring disease progression. Future studies should explore the utility of α-syn SAA in alternative biological specimens, assess its performance across various synucleinopathies and other neurodegenerative diseases, and determine its comparative diagnostic value. Full article

The cellular prion protein (PrP^C) is studied in prion diseases, where its misfolded isoform (PrP^Sc) leads to neurodegeneration. PrP^C has also been implicated in several physiological functions. The protein is abundant in the nervous system, and it is critical for cell signaling in cellular communication, where it acts as a scaffold for various signaling molecules. The Reelin signaling pathway, implicated both in Alzheimer’s and prion diseases, engages Dab1, an adaptor protein influencing APP processing and amyloid beta deposition. Here, we show, using Prnp knockout models (Prnp^0/0), that PrP^C modulates Reelin signaling, affecting Dab1 activation and downstream phosphorylation in both neuronal cultures and mouse brains. Notably, Prnp^0/0 mice showed reduced responsiveness to Reelin, associated with altered Dab1 phosphorylation and Fyn kinase activity. Even though no direct interaction between PrP^C and Reelin/ApoER2 was found, Prnp^0/0 neurons showed lower NCAM levels, a well-established PrP^C interactor. Prion infection further disrupted the Reelin signaling pathway, thus downregulating Dab1 and Reelin receptors and altering Reelin processing, like Alzheimer’s disease pathology. These findings emphasize PrP^C indirect role in Dab1 signaling via the NCAM and Fyn pathways, which influence synaptic function and neurodegeneration in prion diseases. Full article

Prion diseases are classically attributed to the accumulation of protease-resistant prion protein (PrP^Sc); however, recent evidence suggests that alternative misfolded prion conformers and systemic inflammatory factors may also contribute to neurodegeneration. This study investigated whether recombinant moPrP^Res, generated by incubating wild-type mouse PrP^C with bacterial lipopolysaccharide (LPS), can induce prion-like disease in FVB/N female mice, whether LPS alone causes neurodegeneration, and how LPS modulates disease progression in mice inoculated with the Rocky Mountain Laboratory (RML) strain of prions. Wild-type female FVB/N mice were randomized into six subcutaneous treatment groups: saline, LPS, moPrP^Res, moPrP^Res + LPS, RML, and RML + LPS. Animals were monitored longitudinally for survival, body weight, and clinical signs. Brain tissues were analyzed histologically and immunohistochemically for vacuolar degeneration, PrP^Sc accumulation, reactive astrogliosis, and amyloid-β plaque deposition. Recombinant moPrP^Res induced a progressive spongiform encephalopathy characterized by widespread vacuolation and astrogliosis, yet with no detectable PrP^Sc by Western blot or immunohistochemistry. LPS alone triggered a distinct neurodegenerative phenotype, including cerebellar amyloid-β plaque accumulation and terminal-stage spongiosis, with approximately 40% mortality by the end of the study. Co-administration of moPrP^Res and LPS resulted in variable regional pathology and intermediate survival (50% at 750 days post-inoculation). Interestingly, RML + LPS co-treatment led to earlier clinical onset and mortality compared to RML alone; however, vacuolation levels were not significantly elevated and, in some brain regions, were reduced. These results demonstrate that chronic endotoxemia and non-infectious misfolded PrP conformers can independently or synergistically induce key neuropathological hallmarks of prion disease, even in the absence of classical PrP^Sc. Targeting inflammatory signaling and toxic prion intermediates may offer novel therapeutic strategies for prion and prion-like disorders. Full article

Parkinson’s disease and related synucleinopathies, including dementia with Lewy bodies and multiple system atrophy, are characterised by the pathological aggregation of the α-synuclein (aSyn) protein in neuronal and glial cells, leading to cellular dysfunction and neurodegeneration. This review synthesizes knowledge of aSyn biology, including its structure, aggregation mechanisms, cellular interactions, and systemic influences. We highlight the structural diversity of aSyn aggregates, ranging from oligomers to fibrils, their strain-like properties, and their prion-like propagation. While the role of prion-like mechanisms in disease progression remains a topic of ongoing debate, these processes may contribute to the clinical heterogeneity of synucleinopathies. Dysregulation of protein clearance pathways, including chaperone-mediated autophagy and the ubiquitin–proteasome system, exacerbates aSyn accumulation, while post-translational modifications influence its toxicity and aggregation propensity. Emerging evidence suggests that immune responses and alterations in the gut microbiome are key modulators of aSyn pathology, linking peripheral processes—particularly those of intestinal origin—to central neurodegeneration. Advances in biomarker development, such as cerebrospinal fluid assays, post-translationally modified aSyn, and real-time quaking-induced conversion technology, hold promise for early diagnosis and disease monitoring. Furthermore, positron emission tomography imaging and conformation-specific antibodies offer innovative tools for visualising and targeting aSyn pathology in vivo. Despite significant progress, challenges remain in accurately modelling human synucleinopathies, as existing animal and cellular models capture only specific aspects of the disease. This review underscores the need for more reliable aSyn biomarkers to facilitate the development of effective treatments. Achieving this goal requires an interdisciplinary approach integrating genetic, epigenetic, and environmental insights. Full article

Intrinsically disordered proteins (IDPs), such as tau, beta-amyloid (Aβ), and alpha-synuclein (αSyn), are prone to misfolding, resulting in pathological aggregation and propagation that drive neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), and Parkinson’s disease (PD). Misfolded IDPs are prone to aggregate into oligomers and fibrils, exacerbating disease progression by disrupting cellular functions in the central nervous system, triggering neuroinflammation and neurodegeneration. Furthermore, aggregated IDPs exhibit prion-like behavior, acting as seeds that are released into the extracellular space, taken up by neighboring cells, and have a propagating pathology across different regions of the brain. Conventional inhibitors, such as small molecules, peptides, and antibodies, face challenges in stability and blood–brain barrier penetration, limiting their efficacy. In recent years, nanotechnology-based strategies, such as multifunctional nanoplatforms or nanoparticles, have emerged as promising tools to address these challenges. These nanoplatforms leverage tailored designs to prevent or remodel the aggregation of IDPs and reduce associated neurotoxicity. This review discusses recent advances in nanoplatforms designed to target tau, Aβ, and αSyn aggregation, with a focus on their roles in reducing neuroinflammation and neurodegeneration. We examine critical aspects of nanoplatform design, including the choice of material backbone and targeting moieties, which influence interactions with IDPs. We also highlight key mechanisms including the interaction between nanoplatforms and IDPs to inhibit their aggregation, redirect aggregation cascade towards nontoxic, off-pathway species, and disrupt fibrillar structures into soluble forms. We further outline future directions for enhancing IDP clearance, achieving spatiotemporal control, and improving cell-specific targeting. These nanomedicine strategies offer compelling paths forward for developing more effective and targeted therapies for neurodegenerative diseases. Full article

Alzheimer’s disease and other neurodegenerative disorders are characterized by the accumulation of misfolded proteins, such as amyloid-beta, tau, and α-synuclein, which disrupt neuronal function and contribute to cognitive decline. Heparan sulfate proteoglycans, particularly syndecans, play a pivotal role in the seeding, aggregation, and spreading of toxic protein aggregates through endocytic pathways. Among these, syndecan-3 is particularly critical in regulating the internalization of misfolded proteins, facilitating their propagation in a prion-like manner. This review examines the mechanisms by which syndecans, especially SDC3, contribute to the seeding and spreading of pathological protein aggregates in neurodegenerative diseases. Understanding these endocytic pathways provides valuable insights into the potential of syndecans as biomarkers and therapeutic targets for early intervention in Alzheimer’s disease and other related neurodegenerative disorders. Full article

Prion transmission into rodents is essential for understanding prion strains. However, it is often limited by a “species barrier” that makes transmission challenging and complicates the study of animal and human prion diseases. Here, we report that North American deer mice (Peromyscus maniculatus) are susceptible to infection with both human sporadic Creutzfeldt–Jakob disease (sCJD) and chronic wasting disease (CWD). Experimental transmission of both sCJD and CWD in deer mice resulted in 100% attack rates, albeit with differing incubation times, with CWD-inoculated mice taking nearly three times longer than sCJD-inoculated mice to succumb. We observed distinct patterns of spongiform vacuolation and prion-protein deposition in the brain, as well as distinct protein-glycosylation profiles and seeding kinetics in RT-QuIC for each strain. Adaptation on the second passage led to reduced incubation periods and marked strain-specific pathology, as seen predominantly in the cortex in sCJD and the thalamus in CWD. Notably, primary transmission of CWD resulted in infrequent vacuoles and widespread punctate deposits of prion protein in the brain, while diffuse staining and remarkable vacuolation of the thalamus were seen on passage. Prion seeding kinetics for sCJD and CWD were indistinguishable in the second passage; however, the distinct glycosylation patterns seen on immunoblot of the prion protein were maintained. Adaptation also resulted in extraneural dissemination of prion seeding activity distinct to CWD infection. Overall, the ability to transmit both CWD and sCJD to this model, resulting in clear differences in incubation period, biochemical properties, clinical signs, pathology and seeding kinetics, indicates that the model has the potential for use as a tool to investigate atypical cases of sCJD that may indicate CWD spillover to humans. Full article

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons, leading to muscle atrophy, paralysis, and respiratory failure. This comprehensive review synthesizes the current knowledge on ALS pathophysiology, clinical heterogeneity, diagnostic frameworks, and evolving therapeutic strategies. Mechanistically, ALS arises from complex interactions between genetic mutations (e.g., in C9orf72, SOD1, TARDBP (TDP-43), and FUS) and dysregulated cellular pathways, including impaired RNA metabolism, protein misfolding, nucleocytoplasmic transport defects, and prion-like propagation of toxic aggregates. Phenotypic heterogeneity, manifesting as bulbar-, spinal-, or respiratory-onset variants, complicates its early diagnosis, which thus necessitates the rigorous application of the revised El Escorial criteria and emerging biomarkers such as neurofilament light chain. Clinically, ALS intersects with frontotemporal dementia (FTD) in up to 50% of the cases, driven by shared TDP-43 pathology and C9orf72 hexanucleotide expansions. Epidemiological studies have revealed a lifetime risk of 1:350, with male predominance (1.5:1) and peak onset between 50 and 70 years. Disease progression varies widely, with a median survival of 2–4 years post-diagnosis, underscoring the urgency for early intervention. Approved therapies, including riluzole (glutamate modulation), edaravone (antioxidant), and tofersen (antisense oligonucleotide), offer modest survival benefits, while dextromethorphan/quinidine alleviates the pseudobulbar affect. Non-pharmacological treatment advances, such as non-invasive ventilation (NIV), prolong survival by 13 months and improve quality of life, particularly in bulb-involved patients. Multidisciplinary care—integrating physical therapy, respiratory support, nutritional management, and cognitive assessments—is critical to addressing motor and non-motor symptoms (e.g., dysphagia, spasticity, sleep disturbances). Emerging therapies show promise in preclinical models. However, challenges persist in translating genetic insights into universally effective treatments. Ethical considerations, including euthanasia and end-of-life decision-making, further highlight the need for patient-centered communication and palliative strategies. Full article