Mechanisms Of Neurodegeneration Research Articles

Neuroinflammation mediates the progression of neonate hypoxia-ischemia brain damage to Alzheimer’s disease: a bioinformatics and experimental study

BackgroundTraumatic brain injury (TBI) can generally be divided into focal damage and diffuse damage, and neonate Hypoxia-Ischemia Brain Damage (nHIBD) is one of the causes of diffuse damage. Patients with nHIBD are at an increased risk of developing Alzheimer’s disease (AD). However, the shared pathogenesis of patients affected with both neurological disorders has not been fully elucidated.PurposeWe here aim to identify the shared molecular signatures between nHIBD and AD. We used an integrated analysis of the cortex gene expression data, targeting differential expression of genes related to the mechanisms of neurodegeneration and cognitive impairment following traumatic brain injury.MethodsThe gene expression profiles of Alzheimer’s disease (GSE203206) and that of Neonate Hypoxia-Ischemia Brain Damage (GSE23317) were obtained from the Gene Expression Omnibus (GEO) database. After identifying the common differentially expressed genes (DEGs) of Alzheimer’s disease and neonate Hypoxia-Ischemia Brain Damage by limma package analysis, five kinds of analyses were performed on them, namely Gene Ontology (GO) and pathway enrichment analysis, protein–protein interaction network, DEG-transcription factor interactions and DEG-microRNA interactions, protein-drug interactions and protein-disease association analysis, and gene-inflammation association analysis and protein-inflammation association analysis.ResultsIn total, 12 common DEGs were identified including HSPB1, VIM, MVD, TUBB4A, AACS, ANXA6, DIRAS2, RPH3A, CEND1, KALM, THOP1, AREL1. We also identified 11 hub proteins, three central regulatory transcription factors, and three microRNAs encoded by the DEGs. Protein-drug interaction analysis showed that CYC1 and UQCRFS1 are associated with different drugs. Gene-disease association analysis shows Mammary Neoplasms, Neoplasm Metastasis, Schizophrenia, and Brain Ischemia diseases are the most relevant to the hub proteins we identified. Gene-inflammation association analysis shows that the hub gene AREL1 is related to inflammatory response, while the protein-inflammation association analysis shows that the hub proteins AKT1 and MAPK14 are related to inflammatory response.ConclusionThis study provides new insights into the shared molecular mechanisms between AD and nHIBD. These common pathways and hub genes could potentially be used to design therapeutic interventions, reducing the likelihood of Alzheimer’s disease development in survivors of neonatal Hypoxic-Ischemia brain injury.

SARS-CoV-2 and its long-term neurological impact: Unraveling the mechanisms of neurodegeneration and cognitive decline

SARS-CoV-2 and its long-term neurological impact: Unraveling the mechanisms of neurodegeneration and cognitive decline

Exploring the Role of Senescent Cells in Neurodegenerative Pathology: A Window Into Promising Therapeutic Avenues

There is strong evidence that cellular senescence is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Presence of abnormal tau protein in mouse models is implicated in senescence phenotypes leading to cognitive decline, while the significance of pro-inflammatory molecules called senescence-associated secretory phenotypes (SASPs) in inflammation and degeneration highlights its potential importance in disease treatment. Understanding the involvement of senescence in disease progression is vital to develop effective treatment strategies. Clearance of such cells can be performed through senolytics drugs that disturb non-apoptosis pathways. Alternatively, senomorphics involve the suppression of senescence burden, rather than elimination through apoptosis, through the intervention of SASP factors that elicit neuroinflammation and tau toxicity. Other therapeutic approaches involve targeting mitochondrial dysfunction to attenuate neuroinflammation and senescence stressors, thereby preventing the formation of a feedback loop. This review offers insights into the mechanisms of neuro-degeneration driven by cellular senescence in the brain and outlines novel therapeutic strategies to reduce the senescence burden and slow disease progression.

Hydroxyl chalcone derivative DK02 as a multi-target-directed ligand for Alzheimer's disease: A preclinical study in zebrafish.

Alzheimer's disease (AD) is a widespread neurodegenerative condition characterized by amyloid-beta (Aβ) plaques and tau protein aggregates, leading to significant cognitive decline. Existing treatments primarily offer symptomatic relief, underscoring the urgent need for novel therapies that address multiple AD pathways. This study evaluates the efficacy of DK02, a hydroxyl chalcone derivative, in a scopolamine-induced dementia model in zebrafish, hypothesizing that it targets several neurodegenerative mechanisms simultaneously. We employed a blend of experiments, including in silico docking, in vitro enzyme inhibition assays and in vivo zebrafish models, to assess therapeutic effects of DK02. Methods included molecular docking to forecast interaction sites, acetylcholinesterase (AChE) inhibition testing, and various behavioural and histopathological analyses to gauge DK02's cognitive and neuroprotective impacts. DK02 emerged as a potent AChE inhibitor via virtual screening, and significantly enhanced cognitive functions in zebrafish, by improving memory retention and reducing anxiety-like behaviours. DK02 also displayed strong antioxidant properties, reducing oxidative stress-induced neuronal damage. Histopathological analysis confirmed its neuroprotective effects by showing decreased amyloid plaque burden and mitigated structural brain damage. DK02 shows promise as a multi-target-directed ligand for AD, offering a new therapeutic path by simultaneously addressing cholinergic, oxidative and amyloid pathways. Its potential to enhance cognitive functions and curtail neurodegeneration suggests advantages over current symptomatic treatments. Further research into DK02 mechanisms and long-term impacts is essential for its development in AD therapy.

The Neuroprotective Effect of Rooibos Herbal Tea Against Alzheimer's Disease: A Review.

The world is experiencing a demographic shift toward an increasing proportion of elderly persons. Alzheimer's disease (AD) and other neurological disorders are far more likely to develop as people age. AD is a gradual, irreversible, and degenerative brain disorder that progressively deteriorates memory and cognitive function, eventually leading to death. Treatment for AD is the most significant unmet clinical need in neurology. There are no effective treatment options to prevent or reverse the degenerative process. The current medical management focuses primarily on temporarily easing symptoms, with little or no overall improvement. Although genetic predisposition and lifestyle factors influence the risk of neurodegenerative disorders, recent research suggests that dietary polyphenols with solid antioxidant capacities play crucial roles in determining brain health and aging. Aspalathus linearis is used to produce Rooibos, a popular South African herbal tea, which may modulate neurodegenerative mechanisms such as oxidative stress, tau protein, amyloid plaques, inflammation, and metals, all of which have been associated with AD. We reviewed the literature to evaluate the potential neuroprotective effects of Rooibos and its major flavonoids and to understand the underlying molecular mechanisms.

Biological Function Analysis of MicroRNAs and Proteins in the Cerebrospinal Fluid of Patients with Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by alpha-synuclein aggregation into Lewy bodies in the neurons. Cerebrospinal fluid (CSF) is considered the most suited source for investigating PD pathogenesis and identifying biomarkers. While microRNA (miRNA) profiling can aid in the investigation of post-transcriptional regulation in neurodegenerative diseases, information on miRNAs in the CSF of patients with PD remains limited. This review combines miRNA analysis with proteomic profiling to explore the collective impact of CSF miRNAs on the neurodegenerative mechanisms in PD. We constructed separate networks for altered miRNAs and proteomes using a bioinformatics method. Altered miRNAs were poorly linked to biological functions owing to limited information; however, changes in protein expression were strongly associated with biological functions. Subsequently, the networks were integrated for further analysis. In silico prediction from the integrated network revealed relationships between miRNAs and proteins, highlighting increased reactive oxygen species generation, neuronal loss, and neurodegeneration and suppressed ATP synthesis, mitochondrial function, and neurotransmitter release in PD. The approach suggests the potential of miRNAs as biomarkers for critical mechanisms underlying PD. The combined strategy could enhance our understanding of the complex biochemical networks of miRNAs in PD and support the development of diagnostic and therapeutic strategies for precision medicine.

Tau Protein and β-Amyloid Associated with Neurodegeneration in Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis (EAE), a Mouse Model of Multiple Sclerosis.

The levels of β-amyloid precursor protein (β-APP), tau protein, and phosphorylation of tau (p-tau) protein were examined by quantitative immunohistochemistry in the spinal cord sections of mice suffering from experimental autoimmune encephalomyelitis (EAE) in the successive phases of the disease: onset, peak, and chronic. EAE was induced in C57BL/6 mice by immunization with MOG35-55 peptide. The degree of pathological changes was assessed in cross-sections of the entire spinal cord. β-APP expression was observed in the white matter and colocalized with some Iba-1-positive macrophages/microglia. It increased in the peak phase of EAE and remained at the same level in the chronic phase. During the onset and peak phases of EAE, expression of tau protein was observed in nerve fibers and nerve cell perikaryons, with a predominance of nerve fibers, whereas in the chronic phase, tau was labeled mainly in the perikaryons of nerve cells, with its content significantly decreased. P-tau immunostaining was seen only in nerve fibers. The expression of p-tau increased with the progression of EAE, reaching the maximum in the chronic phase. The correlation between these proteins and neurodegeneration/neuroinflammation highlights their potential roles in the progression of neurodegenerative mechanisms in MS.

The Underestimated Role of Iron in Frontotemporal Dementia: A Narrative Review.

The term frontotemporal dementia (FTD) comprises a group of neurodegenerative disorders characterized by the progressive degeneration of the frontal and temporal lobes of the brain with language impairment and changes in cognitive, behavioral and executive functions, and in some cases motor manifestations. A high proportion of FTD cases are due to genetic mutations and inherited in an autosomal-dominant manner with variable penetrance depending on the implicated gene. Iron is a crucial microelement that is involved in several cellular essential functions in the whole body and plays additional specialized roles in the central nervous system (CNS) mainly through its redox-cycling properties. Such a feature may be harmful under aerobic conditions, since it may lead to the generation of highly reactive hydroxyl radicals. Dysfunctions of iron homeostasis in the CNS are indeed involved in several neurodegenerative disorders, although it is still challenging to determine whether the dyshomeostasis of this essential but harmful metal is a direct cause of neurodegeneration, a contributor factor or simply a consequence of other neurodegenerative mechanisms. Unlike many other neurodegenerative disorders, evidence of the dysfunction in brain iron homeostasis in FTD is still scarce; nonetheless, the recent literature intriguingly suggests its possible involvement. The present review aims to summarize what is currently known about the contribution of iron dyshomeostasis in FTD based on clinical, imaging, histological, biochemical and molecular studies, further suggesting new perspectives and offering new insights for future investigations on this underexplored field of research.

Behavioral neuroscience in zebrafish: unravelling the complexity of brain-behavior relationships.

This paper reviews the utility of zebrafish (Danio rerio) as a model system for exploring neurobehavioral phenomena in preclinical research, focusing on physiological processes, disorders, and neurotoxicity biomarkers. A comprehensive review of the current literature was conducted to summarize the various behavioral characteristics of zebrafish. The study examined the etiological agents used to induce neurotoxicity and the biomarkers involved, including Aβ42, tau, MMP-13, MAO, NF-Кβ, and GFAP. Additionally, the different zebrafish study models and their responses to neurobehavioral analysis were discussed. The review identified several key biomarkers of neurotoxicity in zebrafish, each impacting different aspects of neurogenesis, inflammation, and neurodegeneration. Aβ42 was found to alter neuronal growth and stem cell function. Tau's interaction with tubulin affected microtubule stability and led to tauopathies under pathological conditions. MMP-13 was linked to oxidative assault and sensory neuron degeneration. MAO plays a role in neurotransmitter metabolism and neurotoxicity conversion. NF-Кβ was involved in pro-inflammatory pathways, and GFAP was indicative of neuroinflammation and astroglial activation. Zebrafish provide a valuable model for neurobehavioral research, adhering to the "3Rs" philosophy. Their neurotoxicity biomarkers offer insights into the mechanisms of neurogenesis, inflammation, and neurodegeneration. This model system aids in evaluating physiological and pathological conditions, enhancing our understanding of neurobehavioral phenomena and potential therapeutic interventions.

Stat3 mediates Fyn kinase-driven dopaminergic neurodegeneration and microglia activation.

The Alzheimer's disease and Parkinson's disease risk locus FYN kinase is implicated in neurodegeneration and inflammatory signaling. To investigate in vivo mechanisms of Fyn-driven neurodegeneration, we built a zebrafish neural-specific Gal4:UAS model of constitutively active FynY531F signaling. Using in vivo live imaging, we demonstrated that neural FynY531F expression leads to dopaminergic neuron loss and mitochondrial aggregation in 5 day larval brain. Dopaminergic loss coincided with microglia activation and induction of tnfa, il1b and il12a inflammatory cytokine expression. Transcriptome analysis revealed Stat3 signaling as a potential Fyn target. Chemical inhibition experiments confirmed Fyn-driven dopaminergic neuron loss, and the inflammatory response was dependent upon activation of Stat3 and NF-κB pathways. Dual chemical inhibition demonstrated that Stat3 acts synergistically with NF-κB in dopaminergic neuron degeneration. These results identify Stat3 as a novel downstream effector of Fyn signaling in neurodegeneration and inflammation.

Comparison of volumetric brain analysis in subjects with rheumatoid arthritis and ulcerative colitis.

Rheumatoid arthritis (RA) and ulcerative colitis (UC) are two autoimmune diseases where patients report high levels of fatigue, pain, and depression. The effect of systemic inflammation from these diseases is likely affecting the brain, however, it is unknown whether there are measurable neuroanatomical changes and whether these are a contributing factor to these central symptoms. We included 258 RA patients with 774 age and sex matched controls and 249 UC patients with 747 age and sex matched controls in a case control study utilizing the UK Biobank dataset. We used imaging derived phenotypes (IDPs) to determine whether there were differences in (1) hippocampal volume and (2) additional subcortical brain volumes between patients compared to controls and if there were common regions affected between these two diseases. Patients with UC had moderately smaller hippocampi compared to age and sex matched controls (difference: 134.15 mm3, SD ± 64.76, p = 0.035). This result was not seen in RA patients. RA patients had a significantly smaller amygdala volume than age and sex matched controls (difference: 91.27 mm3, SD ± 30.85, p = 0.0021, adjusted p = 0.012). This result was not seen in UC patients. All other subcortical structures analyzed were comparable between the patients and control groups. These results indicate there are subcortical brain differences between UC, RA and controls but different regions of the limbic system are preferentially affected by UC and RA. This study may provide evidence for different neurodegenerative mechanisms in distinct autoimmune diseases.

Choroidal thickness in the eyes of Parkinson's disease patients measured using optical coherence tomography: A systematic review and meta-analysis

BackgroundParkinson's disease (PD) presents a complex etiology involving genetics and environmental factors. Non-motor symptoms often precede motor manifestations. Dopaminergic neuron degeneration, oxidative stress, and vascular changes characterize PD. Retinal changes are studied as potential biomarkers, yet choroidal involvement remains unclear. This review aims to clarify choroidal thickness's role in PD progression for diagnostic advancements. MethodsWe examined PubMed, Scopus, and Embase databases. Depending on the heterogeneity, an appropriate model was used for the meta-analysis. Additionally, meta-regression, publication bias, subgroup analyses, and quality evaluation were carried out. ResultsWe evaluated twelve studies involving 442 PD patients and 608 healthy controls. This study found insignificant differences in choroidal thickness between PD patients and healthy controls. ConclusionChoroidal thickness is influenced by age, axial length, and intraocular pressure, with PD potentially impacting thickness through neurodegenerative mechanisms. However, inconsistencies exist in the findings, warranting further investigation. Future studies should explore the impact of disease severity, medication effects, and other confounding variables on choroidal thickness in PD patients. Additionally, advanced imaging modalities like optical coherence tomography angiography (OCTA) may provide more comprehensive evaluations of choroidal vascular changes in PD.

Lifetime brain atrophy estimated from a single MRI: measurement characteristics and genome-wide correlates.

A measure of lifetime brain atrophy (LBA) obtained from a single magnetic resonance imaging (MRI) scan could be an attractive candidate to boost statistical power in uncovering novel genetic signals and mechanisms of neurodegeneration. We analysed data from five young and old adult cohorts (MRi-Share, Human Connectome Project, UK Biobank, Generation Scotland Subsample, and Lothian Birth Cohort 1936 [LBC1936]) to test the validity and utility of LBA inferred from cross-sectional MRI data, i.e., a single MRI scan per participant. LBA was simply calculated based on the relationship between total brain volume (TBV) and intracranial volume (ICV), using three computationally distinct approaches: the difference (ICV-TBV), ratio (TBV/ICV), and regression-residual method (TBV~ICV). LBA derived with all three methods were substantially correlated with well-validated neuroradiological atrophy rating scales (r = 0.37-0.44). Compared with the difference or ratio method, LBA computed with the residual method most strongly captured phenotypic variance associated with cognitive decline (r = 0.36), frailty (r = 0.24), age-moderated brain shrinkage (r = 0.45), and longitudinally-measured atrophic changes (r = 0.36). LBA computed using a difference score was strongly correlated with baseline (i.e., ICV; r = 0.81) and yielded GWAS signal similar to ICV (rg = 0.75). We performed the largest genetic study of LBA to date (N = 43,110), which was highly heritable (h 2 SNP GCTA = 41% [95% CI = 38-43%]) and had strong polygenic signal (LDSC h 2 = 26%; mean χ2 = 1.23). The strongest association in our genome-wide association study (GWAS) implicated WNT16, a gene previously linked with neurodegenerative diseases such as Alzheimer, and Parkinson disease, and amyotrophic lateral sclerosis. This study is the first side-by-side evaluation of different computational approaches to estimate lifetime brain changes and their measurement characteristics. Careful assessment of methods for LBA computation had important implications for the interpretation of existing phenotypic and genetic results, and showed that relying on the residual method to estimate LBA from a single MRI scan captured brain shrinkage rather than current brain size. This makes this computationally-simple definition of LBA a strong candidate for more powerful analyses, promising accelerated genetic discoveries by maximising the use of available cross-sectional data.

Myelinated Glial Cells: Their Proposed Role in Waste Clearance and Neurodegeneration in Arachnid and Human Brain.

One of the most important goals in biomedical sciences is understanding the causal mechanisms of neurodegeneration. A prevalent hypothesis relates to impaired waste clearance mechanisms from the brain due to reported waste aggregation in the brains of Alzheimer patients, including amyloid-β plaques and neurofibrillary tau tangles. Currently, our understanding of the mechanisms by which waste is removed from the brain is only fragmentary. Here we provide compelling evidence that waste clearance from brain tissue is highly conserved in arachnids and humans. Utilizing RNAscope in situ hybridization, immunohistochemical, ultrastructural, and histological approaches, we demonstrate that cellular debris in spider neurons is engulfed by myelin-forming ependymal glial cells that transect into neuronal somata and form myelin-derived waste-internalizing receptacles. These canal systems channel this debris into the lymphatic system likely in an aquaporin-4 (AQP4) water channel-dependent manner. We provide robust evidence that a similar process may be true in human hippocampus where vast numbers of myelinated AQP4-immunoreactive ependymal glial cells send cellular projections into the somata of neurons and glial cells where they differentiate into waste internalizing receptacles. In the brains of Alzheimer decedents, hypertrophic impairment of these myelinated glial cells leads to the catastrophic obstruction and depletion of neuronal cytoplasm into the ependymal glial cells. At the cellular level, the structural impairment of macroglia leads to swelling myelin protrusions that appear as electron-lucent circular profiles, explaining spongiform abnormalities associated with the neurodegenerative diseases described here. We propose to term this novel type of macroglia-mediated cell death "gliaptosis."

Mitochondrial Quality Control in Alzheimer's Disease: Insights from Caenorhabditis elegans Models.

Alzheimer's disease (AD) is a complex neurodegenerative disorder that is classically defined by the extracellular deposition of senile plaques rich in amyloid-beta (Aβ) protein and the intracellular accumulation of neurofibrillary tangles (NFTs) that are rich in aberrantly modified tau protein. In addition to aggregative and proteostatic abnormalities, neurons affected by AD also frequently possess dysfunctional mitochondria and disrupted mitochondrial maintenance, such as the inability to eliminate damaged mitochondria via mitophagy. Decades have been spent interrogating the etiopathogenesis of AD, and contributions from model organism research have aided in developing a more fundamental understanding of molecular dysfunction caused by Aβ and toxic tau aggregates. The soil nematode C. elegans is a genetic model organism that has been widely used for interrogating neurodegenerative mechanisms including AD. In this review, we discuss the advantages and limitations of the many C. elegans AD models, with a special focus and discussion on how mitochondrial quality control pathways (namely mitophagy) may contribute to AD development. We also summarize evidence on how targeting mitophagy has been therapeutically beneficial in AD. Lastly, we delineate possible mechanisms that can work alone or in concert to ultimately lead to mitophagy impairment in neurons and may contribute to AD etiopathology.

A Novel Human TBCK- Neuronal Cell Model Results in Severe Neurodegeneration and Partial Rescue with Mitochondrial Fission Inhibition.

TBCK syndrome is a rare fatal pediatric neurodegenerative disease caused by biallelic loss-of-function mutations in the TBCK gene. Previous studies by our lab and others have implicated mTOR, autophagy, lysosomes, and intracellular mRNA transport, however the exact primary pathologic mechanism is unknown. This gap has prevented the development of targeted therapies. We employed a human neural progenitor cell line (NPC), ReNcell VM, which can differentiate into neurons and astrocytes, to understand the role of TBCK in mTORC1 activity and neuronal autophagy and cellular mechanisms of pathology. We used shRNA technology to knockdown TBCK in ReNcells. These data showed that loss of TBCK did not inhibit mTORC1 activity in neither NPC nor neurons. Additionally, analysis of eight patient-derived cells and TBCK knock down HeLa cells showed that mTORC1 inhibition is inconsistent across different patients and cell types. We showed that TBCK knockdown in ReNcells affected NPC differentiation to neurons and astrocytes. Specifically, differentiation defects are coupled to cell cycle defects in NPC and increased cell death during differentiation. RNAseq analysis indicated the downregulation of several different neurodevelopmental and differentiation pathways. We observed a higher number of LC3-positive vesicles in the soma and neurites of TBCK knockdown cells. Further, TBCK knockdown altered mitochondrial dynamics and membrane potential in NPC, neurons and astrocytes. We found partial mitochondrial rescue with the mitochondrial fission inhibitor mdivi-1. This work outlines a new Human Cell Model for TBCK-related neurodegeneration and the essential role of mitochondrial health and partial rescue with mitochondrial fission inhibitor. This data, along with human neurons and astrocytes, illuminate mechanisms of neurodegeneration and provide a possible novel therapeutic avenue for affected patients.

Association Between Glaucoma and Brain Structural Connectivity Based on Diffusion Tensor Tractography: A Bidirectional Mendelian Randomization Study.

Glaucoma is a neurodegenerative ocular disease that is accompanied by cerebral damage extending beyond the visual system. Recent studies based on diffusion tensor tractography have suggested an association between glaucoma and brain structural connectivity but have not clarified causality. To explore the causal associations between glaucoma and brain structural connectivity, a bidirectional Mendelian randomization (MR) study was conducted involving glaucoma and 206 diffusion tensor tractography traits. Highly associated genetic variations were applied as instrumental variables and statistical data were sourced from the database of FinnGen and UK Biobank. The inverse-variance weighted method was applied to assess causal relationships. Additional sensitivity analyses were also performed. Glaucoma was potentially causally associated with alterations in three brain structural connectivities (from the SN to the thalamus, from the DAN to the putamen, and within the LN network) in the forward MR analysis, whereas the inverse MR results identified thirteen brain structural connectivity traits with a potential causal relationship to the risk of glaucoma. Both forward and reverse MR analyses satisfied the sensitivity test with no significant horizontal pleiotropy or heterogeneity. This study offered suggestive evidence for the potential causality between the risk of glaucoma and brain structural connectivity. Our findings also provided novel insights into the neurodegenerative mechanism of glaucoma.

An integrative systems-biology approach defines mechanisms of Alzheimer's disease neurodegeneration.

Despite years of intense investigation, the mechanisms underlying neuronal death in Alzheimer's disease, the most common neurodegenerative disorder, remain incompletely understood. To define relevant pathways, we integrated the results of an unbiased, genome-scale forward genetic screen for age-associated neurodegeneration in Drosophila with human and Drosophila Alzheimer's disease-associated multi-omics. We measured proteomics, phosphoproteomics, and metabolomics in Drosophila models of Alzheimer's disease and identified Alzheimer's disease human genetic variants that modify expression in disease-vulnerable neurons. We used a network optimization approach to integrate these data with previously published Alzheimer's disease multi-omic data. We computationally predicted and experimentally demonstrated how HNRNPA2B1 and MEPCE enhance tau-mediated neurotoxicity. Furthermore, we demonstrated that the screen hits CSNK2A1 and NOTCH1 regulate DNA damage in Drosophila and human iPSC-derived neural progenitor cells. Our work identifies candidate pathways that could be targeted to ameliorate neurodegeneration in Alzheimer's disease.

Altered Protein Palmitoylation as Disease Mechanism in Neurodegenerative Disorders.

Palmitoylation, a lipid-based posttranslational protein modification, plays a crucial role in regulating various aspects of neuronal function through altering protein membrane-targeting, stabilities, and protein-protein interaction profiles. Disruption of palmitoylation has recently garnered attention as disease mechanism in neurodegeneration. Many proteins implicated in neurodegenerative diseases and associated neuronal dysfunction, including but not limited to amyloid precursor protein, β-secretase (BACE1), postsynaptic density protein 95, Fyn, synaptotagmin-11, mutant huntingtin, and mutant superoxide dismutase 1, undergo palmitoylation, and recent evidence suggests that altered palmitoylation contributes to the pathological characteristics of these proteins and associated disruption of cellular processes. In addition, dysfunction of enzymes that catalyze palmitoylation and depalmitoylation has been connected to the development of neurological disorders. This review highlights some of the latest advances in our understanding of palmitoylation regulation in neurodegenerative diseases and explores potential therapeutic implications.

Immunoglobulin G and Complement as Major Players in the Neurodegeneration of Multiple Sclerosis.

Multiple Sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) and is termed as one of the most common causes of neurological disability in young adults. Axonal loss and neuronal cell damage are the primary causes of disease progression and disability. Yet, little is known about the mechanism of neurodegeneration in the disease, a limitation that impairs the development of more effective treatments for progressive MS. MS is characterized by the presence of oligoclonal bands and raised levels of immunoglobulins in the CNS. The role of complement in the demyelinating process has been detected in both experimental animal models of MS and within the CNS of affected MS patients. Furthermore, both IgG antibodies and complement activation can be detected in the demyelinating plaques and cortical gray matter lesions. We propose here that both immunoglobulins and complement play an active role in the neurodegenerative process of MS. We hypothesize that the increased CNS IgG antibodies form IgG aggregates and bind complement C1q with high affinity, activating the classical complement pathway. This results in neuronal cell damage, which leads to neurodegeneration and demyelination in MS.