Protein Aggregation Research Articles

Impact of protein aggregation on the immunogenicity of a human monoclonal antibody following pulmonary administration in mice

Spray drying is a widely employed method for generating dry powder formulations for inhalation. Yet, it presents substantial challenges when applied to therapeutic proteins due to stability issues. The formation of protein aggregates during the atomization and the heating steps can diminish protein activity and raise immunogenicity concerns. Here, we assessed the impact of varying levels of protein aggregates generated during spray-drying on the fate and the immunogenicity of the human monoclonal antibody NIP228 following intratracheal administration in mice. Aggregate-free rhodamine labelled NIP228 was spray-dried with or without 1% polysorbate 80 surfactant, resulting in the generation of powder formulations with associated low and high protein aggregate levels, respectively. Confocal imaging highlighted the presence of aggregates in the lungs for both powders but not for the solution, while flow cytometry analysis designated alveolar macrophages as the main immune cells taking up rhod-NIP228 in the lungs with very little involvement of dendritic cells and interstitial macrophages following a single dose administration. Notably, repeated intratracheal administration of the three formulations in mice did not impact the magnitude of the anti-drug antibody response in sera or broncho-alveolar lavages. The pulmonary route appeared to evoke a more robust immune response when compared to subcutaneous administration. Overall, the level of NIP228 aggregation in this study did not appear to be the primary driver of NIP228 immunogenicity following delivery to the lungs in mice, shedding new light on the interplay between protein aggregation and immunogenicity in the context of the pulmonary delivery of therapeutic proteins.

Exploring the rhodanine universe: Design and synthesis of fluorescent rhodanine-based derivatives as anti-fibrillar and anti-oligomer agents against α-synuclein and 2N4R tau

Tau and α-synuclein (α-syn) are prone-to-aggregate proteins that coprecipitate in the brains of Alzheimer’s disease (AD) and Parkinson’s disease (PD) patients. The early-stage oligomers and protofibrils of tau are believed to be strongly linked to human cognitive impairment while the toxic α-syn oligomers are associated with behavioral motor deficits. Therefore, concurrent targeting of both proteinaceous aggregates and their lower dense oligomers are very challenging. Herein, rhodanine-based compounds were designed and synthesized to tackle the fibrils and oligomers of tau and α-syn proteins. In particular, the indole-containing rhodanines 5l and 5r displayed significantly high anti-aggregation activity towards α-syn fibrils by reduction of the thioflavin-T (ThT) fluorescence to lower than 5 %. Moreover, 5r showed a remarkable decrease in the fluorescence of thioflavin-S (ThS) when incubated with the non-phosphorylated tau 0N4R and 2N4R as well as the hyperphosphorylated tau isoform 1N4R, respectively. Transmission electron microscopy (TEM) analyses validated the powerful anti-fibrillar activity of 5l and 5r towards both protein aggregates. In addition, both 5l and 5r highly suppressed 0N4R tau and α-syn oligomer formation using the photo-induced cross-linking of unmodified Protein (PICUP) assay. The fluorescence emission intensity of 5l was quenched to almost half in the presence of both protein fibrils at 510 nm. 5r showed a similar fluorescence response upon binding to 2N4R fibrils while no quenching effect was observed with α-syn aggregates. Ex vivo disaggregation assay using extracted human Aβ plaques was employed to confirm the ability of 5l and 5r to disaggregate the dense fibrils. Both inhibitors showed no promising activity towards the cell-based α-syn inclusion formation. However, another indolyl derivative 5j prevented the α-syn inclusion at 5 µM. Collectively, the indolyl-rhodanine scaffold could act as a building block for further structural optimization to obtain dual targeting disease-modifying candidates for AD and PD.

Effect of high-pressure homogenization optimized by response surface methodology on the techno-functional properties of protein concentrate isolated from date seed

The study investigates the impact of high-pressure homogenization (HPH) optimized using response surface methodology (RSM) on the techno-functional properties of protein concentrate isolated from date seeds. The protein concentrate was subjected to HPH at various pressures (50, 100, and 150 MPa) and protein concentrations (1 %, 2 %, and 3 %) to optimize solubility, emulsifying activity, and antioxidant properties. RSM indicated optimal conditions at 150 MPa and 1 % protein concentration, resulting in significant enhancements in solubility (14.10 % to 43.69 %) and antioxidant activity (60.5 TE/g to 71.67 TE/g). The emulsifying activity index (EAI) increased from 11.92 m²/g to 22.29 m²/g, though the emulsion stability index (ESI) slightly decreased from 17.63 min to 16.15 min. Besides, HPH improved oil-binding capacity (1.73 g/g to 3.02 g/g) while reducing water-binding capacity (2.76 g/g to 1.38 g/g). Structural analysis revealed that HPH caused partial protein unfolding and aggregation, indicated by changes in FTIR spectra, reduced fluorescence intensity, and increased surface sulfhydryl content (1.58 µmol/g to 2.65 µmol/g). These findings highlight HPH as an effective method to enhance the functional properties of date seed protein concentrate for potential applications in the food industry. In addition, the current study can lay a foundation for future HPH applications in other protein-rich by-products such as soybean cake, rapeseed cake, wheat bran, and others.

Effects of interaction between wheat bran dietary fiber and gluten protein on gluten protein aggregation behavior.

Effects of wheat bran dietary fiber (WBDF) as a nutritional additive on flour products quality mainly depends on the interaction between WBDF and gluten protein. In this study, the effects and mechanisms of WBDF with different particle sizes and additive amounts on gluten protein aggregation behavior were investigated. The results showed that the addition of WBDF led to a decrease in free sulfhydryl content, particle size, molecular weight and gluten macromer (GMP) content, an increase in zeta potential and SDS-extractable protein content, and a deterioration in the gluten network morphology compared to the control group, suggesting that the aggregation behavior of gluten protein was inhibited. When WBDF was added at 3 % and 6 %, dilution effect, mechanical shear, steric hindrance, and non-covalent binding were the main mechanisms leading to depolymerization. Further addition of WBDF (9 %, 12 %) inhibited the depolymerization of gluten protein due to competitive hydration and non-covalent binding. However, when WBDF was added at 15 %, the dilution effect, mechanical shear and steric hindrance of WBDF (88 μm < particle size<150 μm) dominated, and their inhibitory of aggregation induced the formation of a loose gluten network structure. In contrast, the weaker mechanical shear and steric hindrance effects of WBDF (particle size<88 μm) mitigated the degradation of gluten network structures by WBDF.

Fabrication and characterization of acidic high internal phase emulsion gels stabilized solely by wheat gluten for plant-based mayonnaise

Plant-based diets are currently gaining more popularity as a means of reducing the environmental footprint and promoting human health. Herein, plant protein-based acidic high internal phase emulsion gels (HIPE gels) were fabricated via a facile one-pot approach using wheat gluten (WG) solely. Pre-dissolving WG in edible vinegar-water solution was contributed to the fabrication of stable emulsion gels. Factors that affect the structure and performance of plant proteins as HIPE gels stabilizers were investigated. The results indicated that the stable HIPE gels could be formed with a vinegar concentration between 5 % and 20 % and a WG concentration of 1.0 %–7.5 % only. Microscopy images reveal that a collaboration of the soluble protein molecules adsorption and protein aggregate Pickering stabilization at oil-water interface, which was turned to form stable HIPE gels. In addition, the resulted HIPE gels exhibited shear thinning behavior, viscoelastic features, and good thixotropic recovery, which provide a similar perceived texture and sensory property for formulating egg-free mayonnaise. These findings provide a useful approach to construct HIPE-based softs from low-cost wheat gluten for preparing plant-based mayonnaise.

Continuity of Short-Time Dynamics Crossing the Liquid-Liquid Phase Separation in Charge-Tuned Protein Solutions.

Liquid-liquid phase separation (LLPS) constitutes a crucial phenomenon in biological self-organization, not only intervening in the formation of membraneless organelles but also triggering pathological protein aggregation, which is a hallmark in neurodegenerative diseases. Employing incoherent quasi-elastic neutron spectroscopy (QENS), we examine the short-time self-diffusion of a model protein undergoing LLPS as a function of phase splitting and temperature to access information on the nanosecond hydrodynamic response to the cluster formation both within and outside the LLPS regime. We investigate the samples as they dissociate into microdroplets of a dense protein phase dispersed in a dilute phase as well as the separated dense and dilute phases obtained from centrifugation. By interpreting the QENS results in terms of the local concentrations in the two phases determined by UV-vis spectroscopy, we hypothesize that the short-time transient protein cluster size distribution is conserved at the transition point while the local volume fractions separate.

Skin and Induced Pluripotent Stem Cells as Biomarkers for Neurodegenerative Diseases

As the global population ages, the rising prevalence of neurodegenerative diseases, characterized by abnormal protein aggregates, presents significant challenges for early diagnosis and disease monitoring. Identifying accessible tissue biomarkers is crucial for advancing our ability to detect and track the progression of these diseases. Among the most promising biomarkers is the skin, which shares a common embryological origin with the brain and central nervous system (CNS). This biological connection positions the skin as a potential reflection of CNS pathology. Over the past decades, gene expression studies have demonstrated that key genes involved in neurodegenerative diseases are also expressed in skin tissues. Genes such as APP, PSEN1, PPA2, PINK1, LRRK2, PLCB4, MAPT, SPAST, and SPG7 are prominent in this regard. Beyond gene expression, proteins related to neurodegenerative diseases—such as α-synuclein, TAU, PARKIN, and prion protein (PrP)—have been isolated from the skin of affected individuals, underscoring the skin’s capacity to mirror neural degeneration. This non-invasive window into neurodegenerative processes is further enhanced by advances in stem cell technology, which have allowed for the generation of human-induced pluripotent stem cells (iPSCs) from patient-derived fibroblasts. These iPSCs offer a valuable model for studying disease mechanisms and developing therapeutic approaches. This review conducts a comprehensive analysis of the literature from databases such as PubMed, Google Scholar, and ResearchGate, emphasizing the unique potential of the skin as a non-invasive biomarker for neurodegenerative diseases. It explores how the skin serves as a bridge between gene expression and disease pathology in both the skin and the CNS. By leveraging this biological connection, the skin emerges as a promising model for enhancing our understanding of neurodegenerative disorders and developing innovative strategies for early detection and treatment. However, significant limitations remain, requiring further validation to establish the specificity and sensitivity of these biomarkers.

Generation and characterization of two induced pluripotent stem cell lines (ICGi052-A and ICGi052-B) from a patient with frontotemporal dementia with parkinsonism-17 associated with the pathological variant c.2013T&gt;G in the MAPT gene

Frontotemporal dementia with parkinsonism-17 is a neurodegenerative disease characterised by pathological aggregation of the tau protein with the formation of neurofibrillary tangles and subsequent neuronal death. The inherited form of frontotemporal dementia can be caused by mutations in several genes, including the MAPT gene on chromosome 17, which encodes the tau protein. As there are currently no medically approved treatments for frontotemporal dementia, there is an urgent need for research using in vitro cell models to understand the molecular genetic mechanisms that lead to the development of the disease, to identify targets for therapeutic intervention and to test potential drugs to prevent neuronal death. Analysis of exome sequencing data from a 46-year-old patient with a clinical diagnosis of Parkinson’s disease revealed the presence of the pathological variant c.2013T&gt;G (rs63750756) in the MAPT gene, which is associated with frontotemporal dementia with parkinsonism-17. By reprogramming the patient’s peripheral blood mononuclear cells, we obtained induced pluripotent stem cells (iPSCs). Two iPSC lines were characterised in detail. Reprogramming was performed by transfection with non-integrating episomal vectors expressing the OCT4, SOX2, KLF4, LIN28, L-MYC and mp53DD proteins. The iPSC lines ICGi052-A and ICGi052-B proliferate stably, form colonies with a morphology characteristic of human pluripotent cells, have a normal diploid karyotype (46,XX), express endogenous alkaline phosphatase and pluripotency markers (OCT4, NANOG, SSEA-4 and TRA-1-60) and are able to differentiate into derivatives of three germ layers: ento-, ecto- and mesoderm. The iPSC lines obtained and characterised in detail in this work represent a unique tool for studying the molecular genetic mechanisms of the pathogenesis of frontotemporal dementia with parkinsonism-17, as well as for testing potential drugs in vitro.

Targeting Protein Misfolding and Aggregation as a Therapeutic Perspective in Neurodegenerative Disorders.

The abnormal deposition and intercellular propagation of disease-specific protein play a central role in the pathogenesis of many neurodegenerative disorders. Recent studies share the common observation that the formation of protein oligomers and subsequent pathological filaments is an essential step for the disease. Synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB) or multiple system atrophy (MSA) are neurodegenerative diseases characterized by the aggregation of the α-synucleinprotein in neurons and/or in oligodendrocytes (glial cytoplasmic inclusions), neuronal loss, and astrogliosis. A similar mechanism of protein Tau-dependent neurodegeneration is a major feature of tauopathies, represented by Alzheimer's disease (AD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Pick's disease (PD). The specific inhibition of the protein misfolding and their interneuronal spreading represents a promising therapeutic strategy against both disease pathology and progression. The most recent research focuses on finding potential applications targeting the pathological forms of proteins responsible for neurodegeneration. This review highlights the mechanisms relevant to protein-dependent neurodegeneration based on the most common disorders and describes current therapeutic approaches targeting protein misfolding and aggregation.

"The More, the Better?": The Impact of Sugar-to-Protein Molar Ratio in Freeze-Dried Monoclonal Antibody Formulations on Protein Stability.

Lyophilization is widely used to ensure the stability of protein drugs by minimizing chemical and physical degradation in the dry solid state. To this end, proteins are typically formulated with sugars that form an amorphous immobilizing matrix and stabilize hydrogen bonds replacing water molecules. The optimal amount of sugar required and protein stability at low excipient-to-protein molar ratios are not well understood. We investigated this by focusing on the physical stability of formulations, reflecting highly concentrated monoclonal antibody (mAb) lyophilizates at low sucrose to mAb ratios between 25:1 and 360:1. Additionally, the impact of different excipient types, buffer concentrations, and polysorbates was studied. The mAb stability was evaluated over up to three months at 25 and 40 °C. We investigated the "the more, the better" approach regarding excipient usage in protein formulation and the existence of a potential stabilizing threshold. Our findings show efficient monomeric content preservation even at low molar ratios, which could be explained based on the water replacement theory. We identified an exponential correlation between the sucrose to protein molar ratio and aggregate formation and found that there is no molar ratio threshold to achieve minimum stabilization. Sucrose demonstrated the best stabilization effect. Both mannitol, used as a cryoprotectant at low concentrations, and arginine reduced aggregation compared to the pure mAb formulation. The higher ionic strength of 5 mM histidine buffer enhanced protein stability compared to that of 0.1 mM histidine buffer, which was more pronounced at lower molar ratios. The addition of polysorbate 20 contributed an additional interfacial stabilizing effect, complementing the cryoprotective and lyoprotective properties of sucrose. Overall, a model could be developed to optimize the quantity of sugar required for protein stabilization and facilitate a more rational design of protein lyophilizates. The molar ratio of sugar to protein for high-concentration mAb products is limited by the acceptable tonicity, but we showed that sufficient stabilization can be achieved even at low molar ratios.

SNG2], a prion form of Cut4/Apc1, confers non-Mendelian inheritance of heterochromatin silencing defect in fission yeast.

Prions represent epigenetic regulator proteins that can self-propagate their structure and confer their misfolded structure and function on normally folded proteins. Like the mammalian prion PrPSc, prions also occur in fungi. While a few prions, like Swi1, affect gene expression, none are shown to affect heterochromatin structure and function. In fission yeast and metazoans, histone methyltransferase Clr4/Suv39 causes H3-Lys9 methylation, which is bound by the chromodomain protein Swi6/HP1 to assemble heterochromatin. Earlier, we showed that sng2-1 mutation in the Cut4 subunit of anaphase-promoting complex abrogates heterochromatin structure due to defective binding and recruitment of Swi6. Here, we demonstrate that the Cut4p forms a non-canonical prion form, designated as [SNG2], which abrogates heterochromatin silencing. [SNG2] exhibits various prion-like properties, e.g. non-Mendelian inheritance, requirement of Hsp proteins for its propagation, de novo generation upon cut4 overexpression, reversible curing by guanidine, cytoplasmic inheritance and formation of infectious protein aggregates, which are dissolved upon overexpression of hsp genes. Interestingly, [SNG2] prion imparts an enhanced tolerance to stress conditions, supporting its role in promoting cell survival under environmental stress during evolution.

Rigidifying the β2-α2 Loop in the Mouse Prion Protein Slows down Formation of Misfolded Oligomers.

Transmissible Spongiform Encephalopathies are fatal neurodegenerative diseases caused by the misfolding of the cellular prion protein (PrPC) into its pathological isoform (PrPSc). Efficient transmission of PrPSc occurs within the same species, but a species barrier limits interspecies transmission. While PrP structure is largely conserved among mammals, variations at the β2-α2 loop are observed, and even minor changes in the amino acid sequence of the β2-α2 loop can significantly affect transmission efficiency. The present study shows that the introduction of the elk/deer-specific amino acid substitutions at positions 169 (Ser to Asn) and 173 (Asn to Thr) into the mouse prion protein, which are associated with the structural rigidity of the β2-α2 loop, has a substantial impact on protein dynamics as well as on the misfolding pathways of the protein. Native state hydrogen-deuterium exchange studies coupled with mass spectrometry, show that the rigid loop substitutions stabilize not only the β2-α2 loop but also the C-terminal end of α3, suggesting that molecular interactions between these two segments are strengthened. Moreover, the energy difference between the native state and multiple misfolding-prone partially unfolded forms (PUFs) present at equilibrium, is increased. The decreased accessibility of the PUFs from the native state leads to a slowing down of the misfolding of the protein. The results of this study provide important insights into the early events of conformational conversion of prion protein into β-rich oligomers, and add to the evidence that the β2-α2 loop is a key determinant in prion protein aggregation.

The neuroinflammatory role of microRNAs in Alzheimer's disease: pathological insights to therapeutic potential.

Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of dementia, contributing to around 60-80% of cases. The main pathophysiology of AD is characterized by an abnormal accumulation of protein aggregates extracellularly (beta-amyloid plaques) and intracellularly (neurofibrillary tangles of hyperphosphorylated tau). However, an increasing number of studies have also suggested neuroinflammation may have a crucial role in precipitating the cascade reactions that result in the development of AD neuropathology. In particular, several studies indicate microRNAs (miRNAs) can act as regulatory factors for neuroinflammation in AD, with potential to affect the occurrence and/or progression of AD inflammation by targeting the expression of multiple genes. Therefore, miRNAs may have potential as therapeutic targets for AD, which requires more research. This article will review the existing studies on miRNAs that have been identified to regulate neuroinflammation, aiming to gain further insights into the specific regulatory processes of miRNAs, highlight the diagnostic and therapeutic potential of miRNAs as biomarkers in AD, as well as current challenges, and suggest the further work to bridge the gap in knowledge to utilize miRNAs as therapeutic targets for AD.

Exploring α-synuclein Interaction Partners and their Potential Clinical Implications for Parkinson's Disease.

Alpha-synuclein aggregates are strongly associated with Parkinson's disease (PD), a degenerative neurological disorder characterized by a progressive loss in motor functions. Our study aimed to unravel the potential interaction partners of α-synuclein for exploring the synucleinpathy of PD related to α-synuclein aggregates. α-synuclein was expressed in E.coli and purified by affinity chromatography followed by isolation and identification of its interaction partners using pulldown assay coupled with LC-MS/MS. The impacts of the identified interaction partners on PD were evaluated based on GSE205450 dataset. Consequently, 157 proteins were identified by the criteria of unique peptide = 5. Four proteins including ACO2, ANT1, ATP5F1B and CKB were confirmed using immunostaining coupled with α-synuclein-pulldown assay. Transcriptomics assay showed that the dominant biological processes influenced by α-synuclein interaction partners with differential expression were energy metabolism. Together with GSE205450, Western blot assay showed that α-synuclein interaction partners involved in energy metabolism were down-regulated in PD patients and the MPTP-lesioned mice. ROC curves indicated their clinical implications as diagnostic indices of PD. Using ANT1 as an example, we found that protein aggregates formed by ANT1 and α-synuclein predominantly solely appeared in the cells and mice with PD-like variations. Thereby, low levels of the interaction partners of α-synuclein associated with energy metabolism were associated with PD pathogenesis via forming protein aggregates. This study provides an insight into developing innovative targets on PD based on synucleinpathy.

G-CSF resistance of ELANE mutant neutropenia depends on SERF1 containing truncated neutrophil elastase aggregates.

Severe congenital neutropenia (SCN) is frequently associated with dominant point mutations in ELANE, the gene encoding neutrophil elastase (NE). Chronic administration of granulocyte colony-stimulating factor (G-CSF) is a first-line treatment of ELANE-mutant (ELANEmut) SCN. However, some ELANEmut patients including patients with ELANE start codon mutations do not respond to G-CSF. Here, through directed granulopoiesis of gene-edited isogenic normal and patient-derived iPSCs, we demonstrate that ELANE start codon mutations suffice to induce G-CSF resistant granulocytic precursor cell death and refractory SCN. ELANE start codon mutated neutrophil precursors express predominantly nuclear N-terminal truncated alternate NE. Unlike G-CSF sensitive ELANE mutations that induce endoplasmic reticulum and unfolded protein response stress, we found that the mutation of the ELANE translation initiation codon resulted in NE aggregates and activated pro-apoptotic aggrephagy as determined by downregulated BAG1 expression, decreased BAG1/BAG3 ratio, NE co-localization with BAG3, and localized expression of autophagic LC3B. We found that SERF1, an RNA-chaperone protein, known to localize in misfolded protein aggregates in neurodegenerative diseases, was highly upregulated and interacted with cytoplasmic NE of mutant neutrophil precursors. Silencing of SERF1 enhanced survival and differentiation of iPSC-derived neutrophil precursors, restoring their responsiveness to G-CSF. These observations provide a mechanistic insight of G-CSF-resistant ELANEmut SCN, revealing targets for therapeutic intervention.

Neuronal fatty acid-binding protein enhances autophagy and suppresses amyloid-β pathology in a Drosophila model of Alzheimer's disease.

Fatty acid-binding proteins (FABPs) are small cytoplasmic proteins involved in intracellular lipid transport and bind free fatty acids, cholesterol, and retinoids. FABP3, the major neuronal FABP in the adult brain, is upregulated in the CSF of patients with Alzheimer's disease (AD). However, the precise role of neuronal FABPs in AD pathogenesis remains unclear. This study investigates the contribution of fabp, the Drosophila homolog of FABP3 and FABP7, to amyloid β (Aβ) pathology using a Drosophila model. Neuronal knockdown of fabp shortened the lifespan of flies and increased age-related protein aggregates in the brain. In an AD model, fabp knockdown in neurons increased Aβ accumulation and Aβ-induced neurodegeneration, whereas fabp overexpression ameliorated Aβ pathology. Notably, fabp overexpression stimulated autophagy, which was inhibited by the knockdown of Eip75B, the Drosophila homolog of the peroxisome proliferator-activated receptor (PPAR). The PPAR activator rosiglitazone restored autophagy impaired by fabp knockdown and reduced fabp knockdown-induced increased Aβ aggregation and cell death. Furthermore, knockdown of either fabp or Eip75B in the wing imaginal disc or adult fly brain reduced the expression of Atg6 and Atg8a. Additionally, treatment of the fabp knockdown AD model flies with polyunsaturated fatty acids, such as docosahexaenoic acid or linoleic acid, partially alleviated cell death in the developing eye, restored impaired autophagy flux, reduced Aβ aggregation, and attenuated Aβ-induced cell death. Our results suggest that Drosophila fabp plays an important role in maintaining protein homeostasis during aging and protects neurons from Aβ-induced cell death by enhancing autophagy through the PPAR pathway. These findings highlight the potential importance of neuronal FABP function in AD pathogenesis.

A special focus on polyadenylation and alternative polyadenylation in neurodegenerative diseases: A systematic review.

Neurodegenerative diseases (NDDs) are one of the prevailing conditions characterized by progressive neuronal loss. Polyadenylation (PA) and alternative polyadenylation (APA) are the two main post-transcriptional events that regulate neuronal gene expression and protein production. This systematic review analyzed the available literature on the role of PA and APA in NDDs, with an emphasis on their contributions to disease development. A comprehensive literature search was performed using the PubMed, Scopus, Cochrane, Google Scholar, Embase, Web of Science, and ProQuest databases. The search strategy was developed based on the framework introduced by Arksey and O'Malley and supplemented by the inclusion and exclusion criteria. The study selection was performed by two independent reviewers. Extraction and data organization were performed in accordance with the predefined variables. Subsequently, quantitative and qualitative analyses were performed. Forty-seven studies were included, related to a variety of NDDs, namely Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Disease induction was performed using different models, including human tissues, animal models, and cultured cells. Most investigations were related to PA, although some were related to APA or both. Amyloid precursor protein (APP), Tau, SNCA, and STMN2 were the major genes identified; most of the altered PA patterns were related to mRNA stability and translation efficiency. This review particularly underscores the key roles of PA and APA in the pathogenesis of NDDs through their mechanisms that contribute to gene expression dysregulation, protein aggregation, and neuronal dysfunction. Insights into these mechanisms may lead to new therapeutic strategies focused on the modulation of PA and APA activities. Further research is required to investigate the translational potential of targeting these pathways for NDD treatment.

Microglial Lyzl4 Facilitates β-Amyloid Clearance in Alzheimer's Disease.

Alzheimer's Disease (AD) is a neurodegenerative condition characterized by the accumulation and deposition of amyloid-β (Aβ) aggregates in the brain. Despite a wealth of research on the toxicity of Aβ and its role in synaptic damage, the mechanisms facilitating Aβ clearance are not yet fully understood. However, microglia, the primary immune cells of the central nervous system, are known to maintain homeostasis through the phagocytic clearance of protein aggregates and cellular debris. In this study, RNA sequencing analysis and live cell functional screens are employed to uncover microglial genetic modifiers related to AD. Lyzl4 is identified, which encodes a c-type lysozyme-like enzyme primarily localized to microglial lysosomes, as a gene significantly upregulated in AD microglia with aging and propose that Lyzl4 upregulation acts as a positive regulator of Aβ clearance. Furthermore, it is found that Lyzl4 overexpression boosts Aβ clearance both in vitro and in vivo, underscoring its potential for mitigating Aβ burden. These novel insights position Lyzl4 as a promising therapeutic target for Alzheimer's disease, paving the way for further exploration into potential AD treatments.

Nanotechnological advancement for the treatment of neurodegenerative disorders

Neurodegenerative disorders are chronic and progressive conditions of the central nervous system. This review work focusses on some of the disorders like Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, and Huntington’s disease which are some of the most prevalent neurodegenerative disorders presenting a substantial challenge on the global health care system. These disorders are characterized by the loss of neurons and the formation of protein aggregates leading to cognitive and motor impairments. The treatment options are available but due to the complex pathophysiology of the disease and the intricate structure of the brain, effective concentrations of drugs are not delivered to brain. Here we discuss some of the recent strategies employed by scientists to enhance the drug delivery and drug targeting to the site of action that is brain for these disorders. Further, nanotechnology-based carrier systems have been discussed which are developed using different natural and synthetic polymers and lipid materials. Owing to many beneficial properties like nanometric size range, physicochemical properties and tunable surface-modifying features, nanocarriers serve as potential systems in the treatment of neurodegenerative diseases as they can easily cross the BBB and reach to the brain in effective concentration. This review article describes neurodegenerative disorders and the limitations associated with their conventional application. Different arrays of nanocarriers such as polymeric nanoparticles, liposomes, Solid Lipid Nanoparticles, Nanostructured Lipid Carriers, and Nanoemulsions have been extensively reviewed. To understand the nanomedicine market, the ongoing clinical trials for various nano-carriers employed to treat these disorders have been compiled and discussed.

Deciphering the Monomeric and Dimeric Conformational Landscapes of the Full-Length TDP-43 and the Impact of the C-Terminal Domain.

The aberrant aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in cells leads to the pathogenesis of multiple fatal neurodegenerative diseases. Decoding the proposed initial transition between its functional dimeric and aggregation-prone monomeric states can potentially design a viable therapeutic strategy, which is presently limited by the lack of structural detail of the full-length TDP-43. To achieve a complete understanding of such a delicate phase space, we employed a multiscale simulation approach that unearths numerous crucial features, broadly summarized in two categories: (1) state-independent features that involve inherent chain collapsibility, rugged polymorphic landscape dictated by the terminal domains, high β-sheet propensity, structural integrity preserved by backbone-based intrachain hydrogen bonds and electrostatic forces, the prominence of the C-terminal domain in the intrachain cross-domain interfaces, and equal participation of hydrophobic and hydrophilic (charged and polar) residues in cross-domain interfaces; and (2) dimerization-modulated characteristics that encompass slower collapsing dynamics, restricted polymorphic landscape, the dominance of side chains in interchain hydrogen bonds, the appearance of the N-terminal domain in the dimer interface, and the prominence of hydrophilic (specifically polar) residues in interchain homo- and cross-domain interfaces. In our work, the ill-known C-terminal domain appears as the most crucial structure-dictating domain, which preferably populates a compact conformation with a high β-sheet propensity in its isolated state stabilized by intrabackbone hydrogen bonds, and these signatures are comparatively faded in its integrated form. Validation of our simulated observables by a complementary spectroscopic approach on multiple counts ensures the robustness of the computationally predicted features of the TDP-43 aggregation landscape.