Search Results (177)

Background/Objectives: Neurodegenerative proteinopathies, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB), are increasingly prevalent worldwide mainly due to population aging. These conditions are marked by complex etiologies, overlapping pathologies, and progressive clinical decline, with significant consequences for patients, caregivers, and healthcare systems. This review aims to synthesize evidence on the healthcare complexities of major neurodegenerative proteinopathies to highlight current knowledge gaps, and to inform future care models, policies, and research directions. Methods: We conducted a comprehensive literature search in PubMed/MEDLINE using combinations of MeSH terms and keywords related to neurodegenerative diseases, proteinopathies, diagnosis, sex, management, treatment, caregiver burden, and healthcare delivery. Studies were included if they addressed the clinical, pathophysiological, economic, or care-related complexities of aging-related neurodegenerative proteinopathies. Results: Key themes identified include the following: (1) multifactorial and unclear etiologies with frequent co-pathologies; (2) long prodromal phases with emerging biomarkers; (3) lack of effective disease-modifying therapies; (4) progressive nature requiring ongoing and individualized care; (5) high caregiver burden; (6) escalating healthcare and societal costs; and (7) the critical role of multidisciplinary and multi-domain care models involving specialists, primary care, and allied health professionals. Conclusions: The complexity and cost of neurodegenerative proteinopathies highlight the urgent need for prevention-focused strategies, innovative care models, early interventions, and integrated policies that support patients and caregivers. Prevention through the early identification of risk factors and prodromal signs is critical. Investing in research to develop effective disease-modifying therapies and improve early detection will be essential to reducing the long-term burden of these disorders. Full article

Transactive response DNA-binding protein of 43 kDa (TDP-43) and tau proteins play critical roles in neurodegenerative diseases, particularly frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD). The co-occurrence of TDP-43 and tau pathologies raises questions about their role in disease progression. This review explores the simultaneous presence of tau and TDP-43 co-pathologies, emphasizing their molecular interactions and the resultant neuropathological implications. Additionally, we provide representative examples of their clinical presentations, neuroimaging, and neuropathological findings associated with FTLD-TDP and FTLD-tau, emphasizing the need for a comprehensive understanding of these intertwined pathologies. We analyze various clinical scenarios, including argyrophilic grain disease (AGD), primary age-related tauopathy (PART), and limbic predominant age-related TDP-43 encephalopathy (LATE), to elucidate the complex relationship between these proteinopathies. From the literature, the co-occurrence of tau and TDP-43 is linked to more severe and poorer clinical outcomes compared to isolated pathologies. This review underscores the necessity of considering co-pathologies in the context of FTLD, as they may act as accelerators of cognitive decline. This highlights the importance of integrated approaches in diagnosing and treating neurodegenerative conditions characterized by tau and TDP-43 misfolding. Understanding the interplay between these molecular markers is vital for advancing therapeutic strategies for such disorders. Full article

Neurodegenerative diseases (NDDs) that are characterized by the accumulation of alpha-synuclein (α-syn) aggregates in both neurons and the non-neuronal cells of the brain are called synucleinopathies. The most common synucleinopathies includes Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). Significant progress has been made in the development of positron emission tomography (PET) radiotracers for synucleinopathies, yielding several α-syn tracers that have entered clinical studies. However, selective α-syn imaging still faces inherent challenges. This review provides a comprehensive overview of the progress in α-syn PET radiotracers from three angles: Alzheimer’s disease (AD)-derived scaffolds, representative compound scaffolds and analogs, and the identification of α-syn tracers through high-throughput screening (HTS). We discuss the characteristics, advantages, and limitations of the tracers for preclinical and clinical application. Finally, future directions in the development of radioligands for proteinopathies are discussed. There is no clinical available PET radiotracer for imaging α-syn aggregates, but these advances have laid a key foundation for non-invasive α-syn imaging and early diagnosis of synucleinopathies. Full article

The molecular imaging of α-synuclein (α-syn) pathology in Parkinson’s disease (PD) and related movement disorders is a clinically unmet need. The aim of this study was to discover and characterize in vitro a radioligand for imaging α-syn pathology. A library of 78 small molecules was developed and screened using recombinant α-syn fibrils and brain homogenates from Alzheimer’s disease (AD) donors. The selection criteria were as follows: Ki_α-syn < 30 nM, Ki_tau and Ki_A-β > 200 nM. Three compounds, GMC-073 (K_iα-syn: 8 nM), GMC-098 (Ki_α-syn: 9.7 nM), and GMC-058 (Ki_α-syn: 22.5 nM), fulfilled the criteria and were radiolabeled with ³H. [³H]GMC-058 was the only compound with negligible binding in controls, and was further evaluated using tissue microarrays, autoradiography on fresh-frozen brain slices, and in vitro saturation binding assay on brain homogenates. [³H]GMC-058 binding co-localized with α-syn inclusions in Parkinson’s disease (PD) and multiple-system atrophy (MSA), with dense A-β plaques in cerebral amyloid angiopathy and AD and with p-tau inclusions in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Specific binding was highest in PSP and CBD. In vitro K_D was highest in AD (5.4 nM), followed by PSP (41 nM) and CBD (75 nM). The K_D in MSA, PD, and controls was >100 nM. [³H]GMC-058 is a novel radioligand displaying a low affinity for aggregated α-syn in tissue, with an in vitro profile also suitable for detecting tau pathology in 4R tauopathies. Full article

This review focuses on the complexities of amyotrophic lateral sclerosis (ALS) onset, highlighting the insidious nature of the disease and the challenges in defining its precise origin and early pathogenic mechanisms. The clinical presentation of ALS is characterised by progressive muscle weakness and wasting, often with widespread fasciculations, reflecting lower motor neuron hyperexcitability. The disease’s pathogenesis involves a prolonged preclinical phase of neuronal proteinopathy, particularly TDP-43 accumulation, which eventually leads to motor neuron death and overt ALS. This review discusses the difficulties in detecting this transition and the implications for early therapeutic intervention. It also addresses the involvement of both the upper and lower motor neuron systems, as well as the importance of following presymptomatic patients with genetic mutations. The significance of understanding the distinct processes of TDP-43 deposition and subsequent neuronal degeneration in developing effective treatments is emphasised. Full article

Familial Alzheimer’s disease (FAD) is a complex multifactorial disorder clinically characterized by cognitive impairment and memory loss. Pathologically, FAD is characterized by intracellular accumulation of the protein fragment Aβ42 (iAβ), hyperphosphorylated microtubule-associated protein TAU (p-TAU), and extensive degeneration of basal forebrain cholinergic neurons of the nucleus basalis of Meynert (NbM) and the medial septal nucleus (MSN), mainly caused by mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and PSEN2 gene. Since the dopaminergic system may contribute to FAD symptoms, alterations in the nigro-hippocampal pathway may be associated with cognitive impairment in FAD. Interestingly, p-α-synuclein (p-α-Syn), Aβ, and p-TAU have been found to coexist in vulnerable regions of postmortem AD brains. However, the mechanism by which Aβ, p-TAU, and α-Syn coexist in DAergic neurons in AD brains has not been determined. We generated PSEN1 I416T dopaminergic-like neurons (DALNs) from I416T menstrual stromal cells (MenSCs) in NeuroForsk 2.0 medium for 7 days and then cultured them in minimal culture medium (MCm) for another 4 days. On day 11, DALNs were analyzed for molecular and pathological markers by flow cytometry and fluorescence microscopy. We found that mutant DALNs showed increased accumulation of iAβ as well as increased phosphorylation of TAU at S202/T205 compared to WT DALNs. Thus, mutant DALNs exhibited typical pathological hallmarks of Alzheimer’s disease. Furthermore, PSEN1 I416T DALNs showed concomitant signs of OS as evidenced by the appearance of oxidized sensor protein DJ-1 (i.e., DJ-1C106-SO₃) and apoptotic markers TP53, pS63-c-JUN, PUMA, and cleavage caspase 3 (CC3). Notably, these DALNs exhibited PD-associated proteins such as intracellular accumulation of α-Syn (detected as aggregates of pS129-α-Syn) and phosphorylation of LRRK2 kinase at residue S935. In addition, mutant DALNs showed a 17.16- and 6.17-fold decrease in DA-induced Ca²⁺ flux, compared to WT DALNs. These observations suggest that iAβ and p-TAU, together with p-α-Syn, and p-LRRK2 kinase, may damage DAergic neurons and thereby contribute to the exacerbation of neuropathologic processes in FAD. Remarkably, the LRRK2 inhibitor PF-06447475 (PF-475) significantly reversed PSEN1 I416T-induced neuropathological markers in DAergic neurons. PF-465 inhibitor reduced iAβ, oxDJ-1C106-SO₃, and p-TAU. In addition, this inhibitor reduced pS935-LRRK2, pS129-αSYN, pS63-c-JUN, and CC3. We conclude that the observed neuroprotective effects of PF-475 are due to direct inhibition of LRRK2 activity and that the LRRK2 protein is upstream of the molecular cascade of apoptosis and proteinopathy. Our results suggest that PF-475 is an effective neuroprotective agent against endogenous PSEN1 I416T-induced neurotoxicity in DALNs coexisting with Parkinson’s disease markers. Therefore, PF-475 may be of great therapeutic value in FAD. 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

Hypothermia (HT) is used clinically for neonatal hypoxic–ischemic encephalopathy (HIE); however, the brain protection is incomplete and selective regional vulnerability and lifelong consequences remain. Refractory damage and impairment with HT cooling/rewarming could result from unchecked or altered persisting cell death and proteinopathy. We tested two hypotheses: (1) HT modifies neurodegeneration type, and (2) intrinsically disordered proteins (IDPs) and encephalopathy cause toxic conformer protein (TCP) proteinopathy neonatally. We studied postmortem human neonatal HIE cases with or without therapeutic HT, neonatal piglets subjected to global hypoxia-ischemia (HI) with and without HT or combinations of HI and quinolinic acid (QA) excitotoxicity surviving for 29–96 h to 14 days, and human oligodendrocytes and neurons exposed to QA for cell models. In human and piglet encephalopathies with normothermia, the neuropathology by hematoxylin and eosin staining was similar; necrotic cell degeneration predominated. With HT, neurodegeneration morphology shifted to apoptosis-necrosis hybrid and apoptotic forms in human HIE, while neurons in HI piglets were unshifting and protected robustly. Oligomers and putative TCPs of α-synuclein (αSyn), nitrated-Syn and aggregated αSyn, misfolded/oxidized superoxide dismutase-1 (SOD1), and prion protein (PrP) were detected with highly specific antibodies by immunohistochemistry, immunofluorescence, and immunoblotting. αSyn and SOD1 TCPs were seen in human HIE brains regardless of HT treatment. αSyn and SOD1 TCPs were detected as early as 29 h after injury in piglets and QA-injured human oligodendrocytes and neurons in culture. Cell immunophenotyping by immunofluorescence showed αSyn detected with antibodies to aggregated/oligomerized protein; nitrated-Syn accumulated in neurons, sometimes appearing as focal dendritic aggregations. Co-localization also showed aberrant αSyn accumulating in presynaptic terminals. Proteinase K-resistant PrP accumulated in ischemic Purkinje cells, and their target regions had PrP-positive neuritic plaque-like pathology. Immunofluorescence revealed misfolded/oxidized SOD1 in neurons, axons, astrocytes, and oligodendrocytes. HT attenuated TCP formation in piglets. We conclude that HT differentially affects brain damage in humans and piglets. HT shifts neuronal cell death to other forms in human while blocking ischemic necrosis in piglet for sustained protection. HI and excitotoxicity also acutely induce formation of TCPs and prion-like proteins from IDPs globally throughout the brain in gray matter and white matter. HT attenuates proteinopathy in piglets but seemingly not in humans. Shifting of cell death type and aberrant toxic protein formation could explain the selective system vulnerability, connectome spreading, and persistent damage seen in neonatal HIE leading to lifelong consequences even after HT treatment. Full article

Aging is the result of various compounding stresses that gradually overcome the homeostatic regulation of the cell, resulting in irreversible damage. This manifests as many acute and chronic conditions, the most common of which are neurodegeneration and dementia. Epidemiological studies have shown significant, strong correlations between viral infection and neurodegenerative diseases. This review overlays the characteristics of viral pathogenesis with the hallmarks of aging to discuss how active and latent viruses contribute to aging. Through our contextualization of myriad basic science papers, we offer explanations for premature aging via viral induction of common stress response pathways. Viruses induce many stresses: dysregulated homeostasis by exogenous viral proteins and overwhelmed protein quality control mechanisms, DNA damage through direct integration and epigenetic manipulation, immune-mediated oxidative stress and immune exhaustion, and general energy theft that is amplified in an aging system. Overall, this highlights the long-term importance of vaccines and antivirals in addition to their acute benefits. Full article

Background/Objectives: TDP-43 mutation-driven Amyotrophic Lateral Sclerosis (ALS) motor neuron disease is one of the most prominent forms (approximately 97%) in cases of sporadic ALS. Dysfunctional autophagy and lysosomal function are the prime mechanisms behind ALS. Mitoxantrone (Mito), a synthetic doxorubicin analog, is an inhibitor of DNA and RNA synthesis/repair via intercalating with nitrogenous bases and inhibiting topoisomerase II. The therapeutic potential of miRNAs associated with disease conditions has also been reported. This study explores the therapeutic potential of Mito along with miRNAs against mutated TDP-43 protein-induced proteinopathy in human-induced pluripotent stem cell (hiPSC)-derived human neural progenitor cells (hNPCs). Methods: HiPSCs mutated for TDP-43 were differentiated into hNPCs and used to explore the therapeutic potential of Mito at a concentration of 1 μM for 24 h (the identified non-cytotoxic dose). The therapeutic effects of Mito on miRNA expression and various cellular parameters such as mitochondrial dynamics, autophagy, and stress granules were assessed using the high-throughput Open Array technique, immunocytochemistry, flow cytometry, immunoblotting, and mitochondrial bioenergetic assay. Results: Mutated TDP-43 protein accumulation causes stress granule formation (G3BP1), mitochondrial bioenergetic dysfunction, SOD1 accumulation, hyperactivated autophagy, and ER stress in hNPCs. The mutated hNPCs also show dysregulation in six miRNAs (miR-543, miR-34a, miR-200c, miR-22, miR-29b, and miR-29c) in mutated hNPCs. A significant restoration of TDP-43 mutation-induced alterations could be witnessed upon the exposure of mutated hNPCs to Mito. Conclusions: Our study indicates that miR-543, miR-29b, miR-22, miR-200c, and miR-34a have antisense therapeutic potential alone and in combination with Mitoxantrone. Full article

Proteinopathies, characterized by the misfolding, aggregation, and deposition of proteins, are hallmarks of various neurodegenerative and systemic diseases. Increasingly, research has highlighted the role of protein misfolding in parasitic infections, unveiling intricate interactions between host and parasite that exacerbate disease pathology and contribute to chronic outcomes. The life cycles of parasitic protozoa, including Plasmodium, Toxoplasmosis, and Leishmania species, are complicated and involve frequent changes between host and vector environments. Their proteomes are severely stressed during these transitions, which calls for highly specialized protein quality control systems. In order to survive harsh intracellular conditions during infection, these parasites have been demonstrated to display unique adaptations in the unfolded protein response, a crucial pathway controlling endoplasmic reticulum stress. In addition to improving parasite survival, these adaptations affect host cell signaling and metabolism, which may jeopardize cellular homeostasis. By causing oxidative stress, persistent inflammation, and disturbance of cellular proteostasis, host–parasite interactions also contribute to proteinopathy. For instance, Plasmodium falciparum disrupts normal protein homeostasis and encourages the accumulation of misfolded proteins by influencing host redox systems involved in protein folding. In addition to interfering with host chaperone systems, the parasitic secretion of effector proteins exacerbates protein misfolding and aggregate formation. Autophagy, apoptosis regulation, organelle integrity, and other vital cellular processes are all disrupted by these pathological protein aggregates. Long-term misfolding and aggregation can cause irreversible tissue damage, which can worsen the clinical course of illnesses like visceral leishmaniasis, cerebral malaria, and toxoplasmosis. Treating parasite-induced proteinopathies is a potentially fruitful area of therapy. According to recent research, autophagy modulators, proteasome enhancers, and small-molecule chaperones may be repurposed to lessen these effects. Pharmacological agents that target the UPR, for example, have demonstrated the ability to decrease parasite survival while also reestablishing host protein homeostasis. Targeting the proteins secreted by parasites that disrupt host proteostasis may also offer a novel way to stop tissue damage caused by proteinopathies. In conclusion, the intersection of protein misfolding and parasitic infections represents a rapidly advancing field of research. Dissecting the molecular pathways underpinning these processes offers unprecedented opportunities for developing innovative therapies. These insights could not only transform the management of parasitic diseases but also contribute to a broader understanding of proteinopathies in infectious and non-infectious diseases alike. Full article

TAR DNA-binding protein 43 kDa (TDP-43) proteinopathies are a group of neurodegenerative diseases (NDs) characterized by the abnormal accumulation of the TDP-43 protein in neurons and glial cells. These proteinopathies are associated with several NDs, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and some forms of Alzheimer’s disease. Yeast models have proven valuable in ND research due to their simplicity, genetic tractability, and the conservation of many cellular processes shared with higher eukaryotes. For several decades, Saccharomyces cerevisiae has been used as a model organism to study the behavior and toxicity of TDP-43, facilitating the identification of genes and pathways that either exacerbate or mitigate its toxic effects. This review will discuss evidence showing that yeast models of TDP-43 exhibit defects in proteostasis, mitochondrial function, autophagy, and RNA metabolism, which are key features of TDP-43-related NDs. Additionally, we will explore how modulating proteins involved in these processes reduce TDP-43 toxicity, aiding in restoring normal TDP-43 function or preventing its pathological aggregation. These findings highlight potential therapeutic targets for the treatment of TDP-43-related diseases. Full article

Multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) are the most common atypical parkinsonism (AP) syndromes. They are clinically characterized by varying combinations of levodopa-poorly responsive parkinsonism, motor, cerebellar, and other signs. They are associated with a wide spectrum of non-motor symptoms, including prominent cognitive impairment such as global cognitive deficits, memory, executive, attentional, visuospatial, language, and non-verbal reasoning dysfunctions. Within the APs, their cognitive functioning is distributed along a continuum from MSA with the least impaired cognitive profile (similar to Parkinson’s disease) to PSP and CBD with the greatest decline in global cognitive and executive domains. Although their pathological hallmarks are different—MSA α-synucleinopathy, CBD, and PSP 4-repeat tauopathies—cognitive dysfunctions in APs show both overlaps and dissimilarities. They are often preceding and anticipate motor dysfunctions, finally contributing to reduced quality of life of patients and caregivers. The present paper will review the current evidence of the prevalence and type of cognitive impairment in these AP syndromes, their neuroimaging, pathogenic backgrounds, and current management options based on extensive literature research. Cognitive dysfunctions in APs are due to disruption of prefronto-subcortical and striato-thalamo-cortical circuitries and multiple essential brain networks. This supports the concept that they are brain network disorders due to complex pathogenic mechanisms related to the basic proteinopathies that are still poorly understood. Therefore, the pathophysiology and pathogenesis of cognitive impairment in APs deserve further elucidation as a basis for early diagnosis and adequate treatment of these debilitating comorbidities. Full article

Depositions of protein aggregates are typical pathological hallmarks of various neurodegenerative diseases (NDs). For example, amyloid-beta (Aβ) and tau aggregates are present in the brain and plasma of patients with Alzheimer’s disease (AD); α-synuclein in Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA); mutant huntingtin protein (Htt) in Huntington’s disease (HD); and DNA-binding protein 43 kD (TDP-43) in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). The same misfolded proteins can be present in multiple diseases in the form of mixed proteinopathies. Since there is no cure for all these diseases, understanding the mechanisms of protein aggregation becomes imperative in modern medicine, especially for developing diagnostics and therapeutics. A Multimer Detection System (MDS) was designed to distinguish and quantify the multimeric/oligomeric forms from the monomeric form of aggregated proteins. As the unique epitope of the monomer is already occupied by capturing or detecting antibodies, the aggregated proteins with multiple epitopes would be accessible to both capturing and detecting antibodies simultaneously, and signals will be generated from the oligomers rather than the monomers. Hence, MDS could present a simple solution for measuring various conformations of aggregated proteins with high sensitivity and specificity, which may help to explore diagnostic and treatment strategies for developing anti-aggregation therapeutics. Full article

Background/Objectives: Traumatic brain injury (TBI) occurs after a sudden mechanical force to the skull and represents a significant public health problem. Initial brain trauma triggers secondary pathophysiological processes that induce structural and functional impairment of the central nervous system, even in the regions distant to the lesion site. Later in life, these changes can be manifested as neurodegenerative sequalae that commonly involve proteinopathies, such as transactive DNA-binding protein 43 (TDP-43). The progression of pathophysiological changes to the spinal cord motor neurons has been detected after repetitive TBI, while such changes have been less investigated after single TBI. Methods: Single TBI was applied over the left parietal cortex of mice by using the lateral fluid percussion injury apparatus and a separate cohort of animals received repetitive mild TBI by weight drop apparatus, with two mild injuries daily, for five days in a row. Mice were sacrificed after single moderate or last mild TBI and their spinal cords were prepared for the analyses. For both types of injury, sham-injured mice were used as a control group. Results: Here, we found an early formation of toxic phosphorylated TDP-43 species on the 3rdday post-injury which, together with TDP-43 cytoplasmic translocation, remained present in the subacute period of 14 days after repetitive mild but not single moderate TBI. During the subacute period following a repetitive brain trauma, we found an increased choline acetyltransferase protein expression and significant microgliosis in the cervical part of the spinal cord, which was not detected after single TBI. Astrogliosis presented similarly after both experimental procedures. Conclusions: This study demonstrates the differences in the spinal cord TDP-43 pathology and inflammation, depending on the brain trauma type, and may contribute to the development of targeted therapeutic strategies. Full article