Α-synuclein Aggregation Research Articles

Catechol-induced covalent modifications modulate the aggregation tendency of α-synuclein: An in-solution and in-silico study.

Parkinson's disease (PD) stands as a challenging neurodegenerative condition characterized by the emergence of Lewy Bodies (LBs), intracellular inclusions within dopaminergic neurons. These LBs harbor various proteins, prominently including α-Synuclein (Syn) aggregates, implicated in disease pathology. A promising avenue in PD treatment involves targeting Syn aggregation. Recent findings from our research have shown that 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethanol (DOPET) possess the ability to impede the formation of Syn fibrils by disrupting the aggregation process. Notably, these compounds primarily engage in noncovalent interactions with the protein, leading to the formation of off-pathway oligomers that deter fibril growth. Through proteolysis studies and mass spectrometry (MS) analysis, we have identified potential covalent modifications of Syn in the presence of DOPAC, although the exact site remains elusive. Employing molecular dynamics simulations, we delved into how DOPAC-induced covalent alterations might affect the mechanism of Syn aggregation. Our findings indicate that the addition of a covalent adduct on certain residues enhances fibril flexibility without compromising its secondary structure stability. Furthermore, in the monomeric state, the modified residue fosters novel bonding interactions, thereby influencing long-range interactions between the N- and C-termini of the protein.

A novel mouse model for investigating α-synuclein aggregates in oligodendrocytes: implications for the glial cytoplasmic inclusions in multiple system atrophy

The aggregated alpha-synuclein (αsyn) in oligodendrocytes (OLGs) is one of the pathological hallmarks in multiple system atrophy (MSA). We have previously reported that αsyn accumulates not only in neurons but also in OLGs long after the administration of αsyn preformed fibrils (PFFs) in mice. However, detailed spatial and temporal analysis of oligodendroglial αsyn aggregates was technically difficult due to the background neuronal αsyn aggregates. The aim of this study is to create a novel mouse that easily enables sensitive and specific detection of αsyn aggregates in OLGs and the comparable analysis of the cellular tropism of αsyn aggregates in MSA brains. To this end, we generated transgenic (Tg) mice expressing human αsyn-green fluorescent protein (GFP) fusion proteins in OLGs under the control of the 2’, 3’-cyclic nucleotide 3’-phosphodiesterase (CNP) promoter (CNP-SNCAGFP Tg mice). Injection of αsyn PFFs in these mice induced distinct GFP-positive aggregates in the processes of OLGs as early as one month post-inoculation (mpi), and their number and size increased in a centripetal manner. Moreover, MSA-brain homogenates (BH) induced significantly more oligodendroglial αsyn aggregates than neuronal αsyn aggregates compared to DLB-BH in CNP-SNCAGFP Tg mice, suggestive of their potential tropism of αsyn seeds for OLGs. In conclusion, CNP-SNCAGFP Tg mice are useful for studying the development and tropism of αsyn aggregates in OLGs and could contribute to the development of therapeutics targeting αsyn aggregates in OLGs.

Usp14 deficiency removes α-synuclein by regulating S100A8/A9 in Parkinson’s disease

Ubiquitin-proteasome system dysfunction triggers α-synuclein aggregation, a hallmark of neurodegenerative diseases, such as Parkinson’s disease (PD). However, the crosstalk between deubiquitinating enzyme (DUBs) and α-synuclein pathology remains unclear. In this study, we observed a decrease in the level of ubiquitin-specific protease 14 (USP14), a DUB, in the cerebrospinal fluid (CSF) of PD patients, particularly females. Moreover, CSF USP14 exhibited a dual correlation with α-synuclein in male and female PD patients. To investigate the impact of USP14 deficiency, we crossed USP14 heterozygous mouse (USP14+/−) with transgenic A53T PD mouse (A53T-Tg) or injected adeno-associated virus (AAV) carrying human α-synuclein (AAV-hα-Syn) in USP14+/− mice. We found that Usp14 deficiency improved the behavioral abnormities and pathological α-synuclein deposition in female A53T-Tg or AAV-hα-Syn mice. Additionally, Usp14 inactivation attenuates the pro-inflammatory response in female AAV-hα-Syn mice, whereas Usp14 inactivation demonstrated opposite effects in male AAV-hα-Syn mice. Mechanistically, the heterodimeric protein S100A8/A9 may be the downstream target of Usp14 deficiency in female mouse models of α-synucleinopathies. Furthermore, upregulated S100A8/A9 was responsible for α-synuclein degradation by autophagy and the suppression of the pro-inflammatory response in microglia after Usp14 knockdown. Consequently, our study suggests that USP14 could serve as a novel therapeutic target in PD.

Polymeric Nanozyme with SOD Activity Capable of Inhibiting Self- and Metal-Induced α-Synuclein Aggregation.

Despite decades of research, Parkinson's disease is still an idiopathic pathology for which no cure has yet been found. This is partly explained by the multifactorial character of most neurodegenerative syndromes, whose generation involves multiple pathogenic factors. In Parkinson's disease, two of the most important ones are the aggregation of α-synuclein and oxidative stress. In this work, we address both issues by synthesizing a multifunctional nanozyme based on grafting a pyridinophane ligand that can strongly coordinate CuII, onto biodegradable PEGylated polyester nanoparticles. The resulting nanozyme exhibits remarkable superoxide dismutase activity together with the ability to inhibit the self-induced aggregation of α-synuclein into amyloid-type fibrils. Furthermore, the combination of the chelator and the polymer produces a cooperative effect whereby the resulting nanozyme can also halve CuII-induced α-synuclein aggregation.

A pilot study on the mechanism of Guasha in treating Parkinson's disease based on molecular level and ultra-trace proteomics analysis

Guasha is a widely applied non-pharmacological therapy of traditional Chinese medicine (TCM), which has been proved to be effective in the treatment of Parkinson's disease (PD). The objective of this study was to explore the mechanisms of Guasha therapy in the pathological processes including neuroinflammation in PD. After 3 Guasha courses, a reduction in α-synuclein aggregation and alleviation of microglia activation were observed in the substantia nigra pars compacta (SNpc). Furthermore, levels of TNF-α, IL-1β and IFN-γ in the SNpc decreased, while plasma TGF-β, IL-4 and IL-10 increased. Moreover, both TH protein and mRNA levels in the SNpc, as well as dopamine levels in the striatum, exhibited an increase. The proteomics analysis results based on plasma-derived exosomes revealed a total of 943 differentially expressed proteins identified. Compared to the model group, the Guasha group screened for 82 differential proteins, with 30 upregulated and 52 downregulated. The improvement of pathological changes in the PD model mice treated with Guasha primarily involves biological processes such as oxidative stress, immune response and inflammation, and cellular structure regulation. It involves signaling pathways related to aldosterone synthesis and secretion, adrenergic signaling in myocardial cells, COVID-19-related inflammatory signaling, and neurotrophic signaling. Collectively, the mechanisms of Guasha for treating PD might be closely related to inhibiting microglial cell activation-mediated neuroinflammation, regulating oxidative stress, cellular structure, aldosterone synthesis and secretion-mediated electrolyte balance, as well as noradrenergic signaling-mediated neuroprotection. These findings provided new insight for Guasha in treating PD and would potentially enhance therapeutic interventions.

Broad proteomics analysis of seeding-induced aggregation of α-synuclein in M83 neurons reveals remodeling of proteostasis mechanisms that might contribute to Parkinson’s disease pathogenesis

Aggregation of misfolded α-synuclein (α-syn) is a key characteristic feature of Parkinson’s disease (PD) and related synucleinopathies. The nature of these aggregates and their contribution to cellular dysfunction is still not clearly elucidated. We employed mass spectrometry-based total and phospho-proteomics to characterize the underlying molecular and biological changes due to α-syn aggregation using the M83 mouse primary neuronal model of PD. We identified gross changes in the proteome that coincided with the formation of large Lewy body-like α-syn aggregates in these neurons. We used protein-protein interaction (PPI)-based network analysis to identify key protein clusters modulating specific biological pathways that may be dysregulated and identified several mechanisms that regulate protein homeostasis (proteostasis). The observed changes in the proteome may include both homeostatic compensation and dysregulation due to α-syn aggregation and a greater understanding of both processes and their role in α-syn-related proteostasis may lead to improved therapeutic options for patients with PD and related disorders.

A cross-sectional study of α-synuclein seed amplification assay in Alzheimer's disease neuroimaging initiative: Prevalence and associations with Alzheimer's disease biomarkers and cognitive function.

Alzheimer's disease (AD) pathology is defined by β-amyloid (Aβ) plaques and neurofibrillary tau, but Lewy bodies (LBs; 𝛼-synuclein aggregates) are a common co-pathology for which effective biomarkers are needed. A validated α-synuclein Seed Amplification Assay (SAA) was used on recent cerebrospinal fluid (CSF) samples from 1638 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, 78 with LB-pathology confirmation at autopsy. We compared SAA outcomes with neuropathology, Aβ and tau biomarkers, risk-factors, genetics, and cognitive trajectories. SAA showed 79% sensitivity and 97% specificity for LB pathology, with superior performance in identifying neocortical (100%) compared to limbic (57%) and amygdala-predominant (60%) LB-pathology. SAA+ rate was 22%, increasing with disease stage and age. Higher Aβ burden but lower CSF p-tau181 associated with higher SAA+ rates, especially in dementia. SAA+ affected cognitive impairment in MCI and Early-AD who were already AD biomarker positive. SAA is a sensitive, specific marker for LB-pathology. Its increase in prevalence with age and AD stages, and its association with AD biomarkers, highlights the clinical importance of α-synuclein co-pathology in understanding AD's nature and progression. SAA shows 79% sensitivity, 97% specificity for LB-pathology detection in AD. SAA positivity prevalence increases with disease stage and age. Higher Aβ burden, lower CSF p-tau181 linked with higher SAA+ rates in dementia. SAA+ impacts cognitive impairment in early disease stages. Study underpins need for wider LB-pathology screening in AD treatment.

A Plant Model of α-Synucleinopathy: Expression of α-Synuclein A53T Variant in Hairy Root Cultures Leads to Proteostatic Stress and Dysregulation of Iron Metabolism.

Synucleinopathies, typified by Parkinson's disease (PD), entail the accumulation of α-synuclein (αSyn) aggregates in nerve cells. Various αSyn mutants, including the αSyn A53T variant linked to early-onset PD, increase the propensity for αSyn aggregate formation. In addition to disrupting protein homeostasis and inducing proteostatic stress, the aggregation of αSyn in PD is associated with an imbalance in iron metabolism, which increases the generation of reactive oxygen species and causes oxidative stress. This study explored the impact of αSyn A53T expression in transgenic hairy roots of four medicinal plants (Lobelia cardinalis, Artemisia annua, Salvia miltiorrhiza, and Polygonum multiflorum). In all tested plants, αSyn A53T expression triggered proteotoxic stress and perturbed iron homeostasis, mirroring the molecular profile observed in human and animal nerve cells. In addition to the common eukaryotic defense mechanisms against proteostatic and oxidative stresses, a plant stress response generally includes the biosynthesis of a diverse set of protective secondary metabolites. Therefore, the hairy root cultures expressing αSyn A53T offer a platform for identifying secondary metabolites that can ameliorate the effects of αSyn, thereby aiding in the development of possible PD treatments and/or treatments of synucleinopathies.

Understanding Genetic Risks: Computational Exploration of Human β-Synuclein nsSNPs and their Potential Impact on Structural Alteration

Synucleins are pivotal in neurodegenerative conditions. Beta-synuclein (β-synuclein) is part of the synuclein protein family alongside alpha-synuclein (α-synuclein) and gamma-synuclein (γ-synuclein). These proteins, found mainly in brain tissue and cancers, are soluble and unstructured. β-synuclein shares significant similarity with α-synuclein, especially in their N-terminus, with a 90% match. However, their aggregation tendencies differ significantly. While α-synuclein aggregation is believed to be counteracted by β-synuclein, which occurs in conditions like Parkinson’s disease, β-synuclein may counteract α-synuclein’s toxic effects on the nervous system, offering potential treatment for neurodegenerative diseases. Under normal circumstances, β-synuclein may guard against disease by interacting with α-synuclein. Yet, in pathological environments with heightened levels or toxic substances, it might contribute to disease. Our research aims to explore potential harmful mutations in the β-synuclein using computational tools to predict their destabilizing impact on protein structure. Consensus analysis revealed rs1207608813 (A63P), rs1340051870 (S72F), and rs1581178262 (G36C) as deleterious. These findings highlight the intricate relationship between nsSNPs and protein function, shedding light on their potential implications in disease pathways. Understanding the structural consequences of nsSNPs is crucial for elucidating their role in pathogenesis and developing targeted therapeutic interventions. Our results offer a robust computational framework for identifying neurodegenerative disorder-related mutations from SNP datasets, potentially reducing the costs associated with experimental characterization.

Red emissive fluorescent carbon dots based on ternary carbon source for imaging α-synuclein fibrils

The misfolding and aggregation of α-synuclein monomers usually cause the occurrence and development of Parkinson’s disease (PD). It is important to develop effective methods for detection of α-synuclein aggregates. Carbon dots (CDs) could be the potential fluorescence probe for this purpose owing to their appreciated optical properties. However, undefined structure of CDs and complicated three-dimensional structure of protein severely hindered the design of fluorescence probe towards protein aggregates. Herein, a red emissive fluorescent amphiphilic CD, named as CL-9, was designed with a high sensitivity to α-synuclein fibrils by a one-step heating process, using the ternary carbon source, including Congo red, l-tryptophan and urea. The CL-9 exhibited turn-on red emissive fluorescence towards α-synuclein fibril, but remained no change towards its monomer. Compared with the original Congo red dye, CL-9 exhibited stronger turn-on red fluorescence towards α-synuclein fibrils with better anti-photobleaching resistance, biocompatibility and signal-to-noise ratio. The CL-9 was successful as a fluorescent probe to image α-synuclein fibrils in NL-5901 C. elegans. The present study provided a feasible approach using the multiple carbon sources to construct the CDs based fluorescence probe targeting amyloid proteins.

Unraveling the mechanistic interplay of mediators orchestrating the neuroprotective potential of harmine.

Neurodegenerative diseases (NDDs) encompass a range of conditions characterized by the specific dysfunction and continual decline of neurons, glial cells, and neural networks within the brain and spinal cord. The majority of NDDs exhibit similar underlying causes, including oxidative stress, neuroinflammation, and malfunctioning of mitochondria. Elevated levels of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), alongside decreased expression of brain-derived neurotrophic factor (BDNF) and glutamate transporter subtype 1 (GLT-1), constitute significant factors contributing to the pathogenesis of NDDs. Additionally, the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene has emerged as a significant target for the treatment of NDDs at the preclinical level. It significantly contributes to developmental brain defects, early onset neurodegeneration, neuronal loss, and dementia in Down syndrome. Moreover, an impaired ubiquitin-proteosome system (UPS) also plays a pathological role in NDDs. Malfunctioning of UPS leads to abnormal protein buildup or aggregation of α-synuclein. α-Synuclein is a highly soluble unfolded protein that accumulates in Lewy bodies and Lewy neurites in Parkinson's disease and other synucleinopathies. Recent research highlights the promising potential of natural products in combating NDDs relative to conventional therapies. Alkaloids have emerged as promising candidates in the fight against NDDs. Harmine is a tricyclic β-carboline alkaloid (harmala alkaloid) with one indole nucleus and a six-membered pyrrole ring. It is extracted from Banisteria caapi and Peganum harmala L. and exhibits diverse pharmacological properties, encompassing neuroprotective, antioxidant, anti-inflammatory, antidepressant, etc. Harmine has been reported to mediate its neuroprotective via reducing the level of inflammatory mediators, NADPH oxidase, AChE, BChE and reactive oxygen species (ROS). Whereas, it has been observed to increase the levels of BDNF, GLT-1 and anti-oxidant enzymes, along with protein kinase-A (PKA)-mediated UPS activation. This review aims to discuss the mechanistic interplay of various mediators involved in the neuroprotective effect of harmine.

Dimethylsulfoniopropionate (DMSP) Increases Longevity and Mitochondrial Function in Caenorhabditis elegans: Implications for the Role of the Global Sulfur Cycle in Terrestrial Ecosystems.

Dimethylsulfoniopropionate (DMSP) is a compound synthesized by marine phytoplankton that contributes to the oceanic sulfur cycle. Interestingly, DMSP has also been found in algal species and several terrestrial plants, forming part of the global sulfur cycle. However, compared to its role in the marine environment, the impact of DMSP on terrestrial ecosystems remains relatively unexplored. In this study, DMSP was shown to promote longevity and prevent age-associated functional decline in Caenorhabditis elegans (C. elegans), a soil-dwelling organism. DMSP decreased mitochondrial content and improved mitochondrial function in C. elegans at the old stage, which was via enhancing autophagy flux. It was demonstrated that DMSP significantly increased the expression of autophagy and mitophagy genes during aging. Furthermore, DMSP protected against Parkinson's disease (PD) induced by α-synuclein (α-syn) aggregation via autophagy. Mechanistic studies showed that DMSP directly activated nuclear translocation of the Skinhead-1 (SKN-1) transcription factor from the cytoplasm. Moreover, SKN-1 was involved in DMSP-induced autophagy and played a key role in lifespan extension and α-syn clearance in C. elegans. In conclusion, DMSP delays physiological aspects of aging in C. elegans, providing insights into the interplay between the global sulfur cycle and terrestrial organisms.

Understanding the (epi)genetic dysregulation in Parkinson's disease through an integrative brain competitive endogenous RNA network

Parkinson’s disease (PD) is a rapidly growing neurodegenerative disorder characterized by dopaminergic neuron loss in the substantia nigra pars compacta (SN) and aggregation of α-synuclein. Its aetiology involves a multifaceted interplay among genetic, environmental, and epigenetic factors. We integrated brain gene expression data from PD patients to construct a comprehensive regulatory network encompassing messenger RNAs (mRNAs), microRNAs (miRNAs), circular RNAs (circRNAs) and, for the first time, RNA binding proteins (RBPs). Expression data from the SN of PD patients and controls were systematically selected from public databases to identify combined differentially expressed genes (DEGs). Brain co-expression analysis revealed modules comprising significant DEGs that function cooperatively. The relationships among co-expressed DEGs, miRNAs, circRNAs, and RBPs revealed an intricate competitive endogenous RNA (ceRNA) network responsible for post-transcriptional dysregulation in PD. Many genes in the ceRNA network, including the TOMM20 and HMGCR genes, overlap with the most relevant genes in our previous Alzheimer’s disease-associated ceRNA network, suggesting common underlying mechanisms between both conditions. Moreover, in the ceRNA subnetwork, the RBP Aly/REF export factor (ALYREF), which acts as an RNA 5-methylcytosine(m5C)-binding protein, stood out. Our data sheds new light on the potential role of brain ceRNA networks in PD pathogenesis.

Gut microbiota produces biofilm-associated amyloids with potential for neurodegeneration.

Age-related neurodegenerative diseases involving amyloid aggregation remain one of the biggest challenges of modern medicine. Alterations in the gastrointestinal microbiome play an active role in the aetiology of neurological disorders. Here, we dissect the amyloidogenic properties of biofilm-associated proteins (BAPs) of the gut microbiota and their implications for synucleinopathies. We demonstrate that BAPs are naturally assembled as amyloid-like fibrils in insoluble fractions isolated from the human gut microbiota. We show that BAP genes are part of the accessory genomes, revealing microbiome variability. Remarkably, the abundance of certain BAP genes in the gut microbiome is correlated with Parkinson's disease (PD) incidence. Using cultured dopaminergic neurons and Caenorhabditis elegans models, we report that BAP-derived amyloids induce α-synuclein aggregation. Our results show that the chaperone-mediated autophagy is compromised by BAP amyloids. Indeed, inoculation of BAP fibrils into the brains of wild-type mice promote key pathological features of PD. Therefore, our findings establish the use of BAP amyloids as potential targets and biomarkers of α-synucleinopathies.

Novel 4-triazole phenyl amide (4-TPA) molecules: Potent promoters of α-synuclein fibril disassembly

Parkinson's disease profoundly compromises patients' daily lives, and the disassembly of α-synuclein aggregates, a primary pathological factor, represents a promising therapeutic approach. In this study, we conducted a systematic screening and optimization process to identify the novel scaffold B37, a 4-triazolyl-phenylamine derivative, exhibiting a potent disassembly activity of 1.1 μM against α-synuclein preformed fibrils. Notably, B37 demonstrated significant neuroprotective effects, ameliorated autophagic dysfunction induced by preformed fibrils, mitigated oxidative stress, and restored the co-localization of preformed fibrils with lysosomes. Transmission electron microscopy corroborated its in vitro disassembly function. Pharmacokinetic profiling revealed favorable parameters with a receptible blood-brain barrier permeability. B37 emerges as a promising lead compound for further optimization, aiming to develop a highly effective agent targeting the disassembly of α-synuclein aggregates to treat neurodegenerative diseases like Parkinson's disease.

Nicotine-mediated therapy for Parkinson's disease in transgenic Caenorhabditis elegans model.

Parkinson's disease resultant in the degeneration of Dopaminergic neurons and accumulation of α-synuclein in the substantia nigra pars compacta. The synthetic therapeutics for Parkinson's disease have moderate symptomatic benefits but cannot prevent or delay disease progression. In this study, nicotine was employed by using transgenic Caenorhabditis elegans Parkinson's disease models to minimize the Parkinson's disease symptoms. The results showed that the nicotine at 100, 150, and 200 μM doses reduced degeneration of Dopaminergic neurons caused by 6-hydroxydopamine (14, 33, and 40%), lowered the aggregative toxicity of α-synuclein by 53, 56, and 78%, respectively. The reduction in food-sensing behavioral disabilities of BZ555 was observed to be 18, 49, and 86%, respectively, with nicotine concentrations of 100 μM, 150 μM, and 200 μM. Additionally, nicotine was found to enhance Daf-16 nuclear translocation by 14, 31, and 49%, and dose-dependently increased SOD-3 expression by 10, 19, and 23%. In summary, the nicotine might a promising therapy option for Parkinson's disease.

Neurotransmitter accumulation and Parkinson's disease-like phenotype caused by anion channelrhodopsin opto-controlled astrocytic mitochondrial depolarization in substantia nigra pars compacta.

Parkinson's disease (PD) is a mitochondria-related neurodegenerative disease characterized by locomotor deficits and loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Majority of PD research primarily focused on neuronal dysfunction, while the roles of astrocytes and their mitochondria remain largely unexplored. To bridge the gap and investigate the roles of astrocytic mitochondria in PD progression, we constructed a specialized optogenetic tool, mitochondrial-targeted anion channelrhodopsin, to manipulate mitochondrial membrane potential in astrocytes. Utilizing this tool, the depolarization of astrocytic mitochondria within the SNc in vivo led to the accumulation of γ-aminobutyric acid (GABA) and glutamate in SNc, subsequently resulting in excitatory/inhibitory imbalance and locomotor deficits. Consequently, in vivo calcium imaging and interventions of neurotransmitter antagonists demonstrated that GABA accumulation mediated movement deficits of mice. Furthermore, 1h/day intermittent astrocytic mitochondrial depolarization for 2 weeks triggered spontaneous locomotor dysfunction, α-synuclein aggregation, and the loss of DA neurons, suggesting that astrocytic mitochondrial depolarization was sufficient to induce a PD-like phenotype. In summary, our findings suggest the maintenance of proper astrocytic mitochondrial function and the reinstatement of a balanced neurotransmitter profile may provide a new angle for mitigating neuronal dysfunction during the initial phases of PD.

Sex-dependent interactions between prodromal intestinal inflammation and LRRK2 G2019S in mice promote endophenotypes of Parkinson’s disease

Gastrointestinal (GI) disruptions and inflammatory bowel disease (IBD) are commonly associated with Parkinson’s disease (PD), but how they may impact risk for PD remains poorly understood. Herein, we provide evidence that prodromal intestinal inflammation expedites and exacerbates PD endophenotypes in rodent carriers of the human PD risk allele LRRK2 G2019S in a sex-dependent manner. Chronic intestinal damage in genetically predisposed male mice promotes α-synuclein aggregation in the substantia nigra, loss of dopaminergic neurons and motor impairment. This male bias is preserved in gonadectomized males, and similarly conferred by sex chromosomal complement in gonadal females expressing human LRRK2 G2019S. The early onset and heightened severity of neuropathological and behavioral outcomes in male LRRK2 G2019S mice is preceded by increases in α-synuclein in the colon, α-synuclein-positive macrophages in the colonic lamina propria, and loads of phosphorylated α-synuclein within microglia in the substantia nigra. Taken together, these data reveal that prodromal intestinal inflammation promotes the pathogenesis of PD endophenotypes in male carriers of LRRK2 G2019S, through mechanisms that depend on genotypic sex and involve early accumulation of α-synuclein in myeloid cells within the gut.

Aberrant CHCHD2-associatedmitochondriopathy in Kii ALS/PDC astrocytes.

Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as asignificantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.

Insights into Calpain Activation and Rho-ROCK Signaling in Parkinson's Disease and Aging.

Parkinson's disease (PD), a progressive neurodegenerative disease, has no cure, and current therapies are not effective at halting disease progression. The disease affects mid-brain dopaminergic neurons and, subsequently, the spinal cord, contributing to many debilitating symptoms associated with PD. The GTP-binding protein, Rho, plays a significant role in the cellular pathology of PD. The downstream effector of Rho, Rho-associated kinase (ROCK), plays multiple functions, including microglial activation and induction of inflammatory responses. Activated microglia have been implicated in the pathology of many neurodegenerative diseases, including PD, that initiate inflammatory responses, leading to neuron death. Calpain expression and activity is increased following glial activation, which triggers the Rho-ROCK pathway and induces inflammatory T cell activation and migration as well as mediates toxic α-synuclein (α-syn) aggregation and neuron death, indicating a pivotal role for calpain in the inflammatory and degenerative processes in PD. Increased calpain activity and Rho-ROCK activation may represent a new mechanism for increased oxidative damage in aging. This review will summarize calpain activation and the role of the Rho-ROCK pathway in oxidative stress and α-syn aggregation, their influence on the neurodegenerative process in PD and aging, and possible strategies and research directions for therapeutic intervention.