Enteric α-synuclein impairs intestinal epithelial barrier through caspase-1-inflammasome signaling in Parkinson’s disease before brain pathology

AbstractsBowel inflammation, impaired intestinal epithelial barrier (IEB), and gut dysbiosis could represent early events in Parkinson’s disease (PD). This study examined, in a descriptive manner, the correlation among enteric α-synuclein, bowel inflammation, impairments of IEB and alterations of enteric bacteria in a transgenic (Tg) model of PD before brain pathology. Human A53T α-synuclein Tg mice were sacrificed at 3, 6, and 9 months of age to evaluate concomitance of enteric inflammation, IEB impairments, and enteric bacterial metabolite alterations during the early phases of α-synucleinopathy. The molecular mechanisms underlying the interplay between α-synuclein, activation of immune/inflammatory responses and IEB alterations were investigated with in vitro experiments in cell cultures. Tg mice displayed an increase in colonic levels of IL-1β, TNF, caspase-1 activity and enteric glia activation since 3 months of age. Colonic TLR-2 and zonulin-1 expression were altered in Tg mice as compared with controls. Lipopolysaccharide levels were increased in Tg animals at 3 months, while fecal butyrate and propionate levels were decreased. Co-treatment with lipopolysaccharide and α-synuclein promoted IL-1β release in the supernatant of THP-1 cells. When applied to Caco-2 cells, the THP-1-derived supernatant decreased zonulin-1 and occludin expression. Such an effect was abrogated when THP-1 cells were incubated with YVAD (caspase-1 inhibitor) or when Caco-2 were incubated with anakinra, while butyrate incubation did not prevent such decrease. Taken together, early enteric α-synuclein accumulation contributes to compromise IEB through the direct activation of canonical caspase-1-dependent inflammasome signaling. These changes could contribute both to bowel symptoms as well as central pathology.

Gaps and roadmap of novel neuromodulation targets for treatment of gait in Parkinson’s disease

Gait issues in Parkinson’s disease (PD) are common and can be highly disabling. Although levodopa and deep brain stimulation (DBS) of the subthalamic nucleus and the globus pallidus internus have been established therapies for addressing the motor symptoms of PD, their effects on gait are less predictable and not well sustained with disease progression. Given the high prevalence of gait impairment in PD and the limitations in currently approved therapies, there has been considerable interest in alternative neuromodulation targets and techniques. These have included DBS of pedunculopontine nucleus and substantia nigra pars reticulata, spinal cord stimulation, non-invasive modulation of cortical regions and, more recently, vagus nerve stimulation. However, successes and failures have also emerged with these approaches. Current gaps and controversies are related to patient selection, optimal electrode placement within the target, placebo effects and the optimal programming parameters. Additionally, recent advances in pathophysiology of oscillation dynamics have driven new models of closed-loop DBS systems that may or may not be applicable to gait issues. Our aim is to describe approaches, especially neuromodulation procedures, and emerging challenges to address PD gait issues beyond subthalamic nucleus and the globus pallidus internus stimulation.

Thalamic white matter macrostructure and subnuclei volumes in Parkinson’s disease depression

Depression is a common non-motor feature of Parkinson’s disease (PD) which confers significant morbidity and is challenging to treat. The thalamus is a key component in the basal ganglia-thalamocortical network critical to the pathogenesis of PD and depression but the precise thalamic subnuclei involved in PD depression have not been identified. We performed structural and diffusion-weighted imaging (DWI) on 76 participants with PD to evaluate the relationship between PD depression and grey and white matter thalamic subnuclear changes. We used a thalamic segmentation method to divide the thalamus into its 50 constituent subnuclei (25 each hemisphere). Fixel-based analysis was used to calculate mean fibre cross-section (FC) for white matter tracts connected to each subnucleus. We assessed volume and FC at baseline and 14–20 months follow-up. A generalised linear mixed model was used to evaluate the relationship between depression, subnuclei volume and mean FC for each thalamic subnucleus. We found that depression scores in PD were associated with lower right pulvinar anterior (PuA) subnucleus volume. Antidepressant use was associated with higher right PuA volume suggesting a possible protective effect of treatment. After follow-up, depression scores were associated with reduced white matter tract macrostructure across almost all tracts connected to thalamic subnuclei. In conclusion, our work implicates the right PuA as a relevant neural structure in PD depression and future work should evaluate its potential as a therapeutic target for PD depression.

Insights into the multifaceted role of circular RNAs: implications for Parkinson’s disease pathogenesis and diagnosis

Parkinson’s disease (PD) is a complex, age-related, neurodegenerative disease whose etiology, pathology, and clinical manifestations remain incompletely understood. As a result, care focuses primarily on symptoms relief. Circular RNAs (circRNAs) are a large class of mostly noncoding RNAs that accumulate with aging in the brain and are increasingly shown to regulate all aspects of neuronal and glial development and function. They are generated by the spliceosome through the backsplicing of linear RNA. Although their biological role remains largely unknown, they have been shown to regulate transcription and splicing, act as decoys for microRNAs and RNA binding proteins, used as templates for translation, and serve as scaffolding platforms for signaling components. Considering that they are stable, diverse, and detectable in easily accessible biofluids, they are deemed promising biomarkers for diagnosing diseases. CircRNAs are differentially expressed in the brain of patients with PD, and growing evidence suggests that they regulate PD pathogenetic processes. Here, the biogenesis, expression, degradation, and detection of circRNAs, as well as their proposed functions, are reviewed. Thereafter, research linking circRNAs to PD-related processes, including aging, alpha-synuclein dysregulation, neuroinflammation, and oxidative stress is highlighted, followed by recent evidence for their use as prognostic and diagnostic biomarkers for PD.

Cofilin 1 promotes the pathogenicity and transmission of pathological α-synuclein in mouse models of Parkinson’s disease

The pathological hallmark of Parkinson’s disease (PD) is the presence of Lewy bodies (LBs) with aggregated α-synuclein being the major component. The abnormal α-synuclein aggregates transfer between cells, recruit endogenous α-synuclein into toxic LBs, and finally trigger neuronal injury. However, the molecular mechanisms mediating the aggregation and transmission of pathological α-synuclein remain unknown. Previously we found that cofilin 1, a member of the actin-binding protein, promotes the aggregation and pathogenicity of α-synuclein in vitro. Here we further investigated the effect of cofilin 1 in mouse models of PD. We found that the mixed fibrils composed of cofilin 1 and α-synuclein are more pathogenic to mice and more prone to propagation than pure α-synuclein fibrils. Overexpression of cofilin 1 enhances the seeding and spreading of α-synuclein aggregates, and induces PD-like behavioral impairments in mice. Together, these results illustrate the important role of cofilin 1 in the pathogenicity and transmission of α-synuclein during the onset and progression of PD.

Biallelic expansion in RFC1 as a rare cause of Parkinson’s disease

An intronic expansion (AAGGG)exp in the RFC1 gene has recently been shown to cause recessively inherited cerebellar ataxia, neuropathy, and vestibular areflexia syndrome and, furthermore, a few patients with ataxia and parkinsonism have been reported. We investigated 569 Finnish patients with medicated parkinsonism for RFC1 and found biallelic (AAGGG)exp in three non-consanguineous patients with clinically confirmed Parkinson’s disease without ataxia suggesting that RFC1-related disorders include Parkinson’s disease as well.

Lewy body disease or diseases with Lewy bodies?

The current nosological concept of α-synucleinopathies characterized by the presence of Lewy bodies (LBs) includes Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), and dementia with Lewy bodies (DLB), for which the term “Lewy body disease” (LBD) has recently been proposed due to their considerable clinical and pathological overlap. However, even this term does not seem to describe the true nature of this group of diseases. The subsequent discoveries of α-synuclein (αSyn), SNCA gene, and the introduction of new immunohistochemical methods have started intensive research into the molecular-biological aspects of these diseases. In light of today’s knowledge, the role of LBs in the pathogenesis and classification of these nosological entities remains somewhat uncertain. An increasingly more important role is attributed to other factors as the presence of various LBs precursors, post-translational αSyn modifications, various αSyn strains, the deposition of other pathological proteins (particularly β-amyloid), and the discovery of selective vulnerability of specific cells due to anatomical configuration or synaptic dysfunction. Resulting genetic inputs can undoubtedly be considered as the main essence of these factors. Molecular–genetic data indicate that not only in PD but also in DLB, a unique genetic architecture can be ascertained, predisposing to the development of specific disease phenotypes. The presence of LBs thus remains only a kind of link between these disorders, and the term “diseases with Lewy bodies” therefore results somewhat more accurate.

Functional connectivity in Parkinson’s disease candidates for deep brain stimulation

This study aimed to identify functional neuroimaging patterns anticipating the clinical indication for deep brain stimulation (DBS) in patients with Parkinson’s disease (PD). A cohort of prospectively recruited patients with PD underwent neurological evaluations and resting-state functional MRI (RS-fMRI) at baseline and annually for 4 years. Patients were divided into two groups: 19 patients eligible for DBS over the follow-up and 41 patients who did not meet the criteria to undergo DBS. Patients selected as candidates for DBS did not undergo surgery at this stage. Sixty age- and sex-matched healthy controls performed baseline evaluations. Graph analysis and connectomics assessed global and local topological network properties and regional functional connectivity at baseline and at each time point. At baseline, network analysis showed a higher mean nodal strength, local efficiency, and clustering coefficient of the occipital areas in candidates for DBS over time relative to controls and patients not eligible for DBS. The occipital hyperconnectivity pattern was confirmed by regional analysis. At baseline, a decreased functional connectivity between basal ganglia and sensorimotor/frontal networks was found in candidates for DBS compared to patients not eligible for surgery. In the longitudinal analysis, patient candidate for DBS showed a progressively decreased topological brain organization and functional connectivity, mainly in the posterior brain networks, and a progressively increased connectivity of basal ganglia network compared to non-candidates for DBS. RS-fMRI may support the clinical indication to DBS and could be useful in predicting which patients would be eligible for DBS in the earlier stages of PD.

Specific immune status in Parkinson’s disease at different ages of onset

Recent evidence suggests that innate and adaptive immunity play a crucial role in Parkinson’s disease (PD). However, studies regarding specific immune cell classification in the peripheral blood in PD remain lacking. Therefore, we aimed to explore the different immune status in patients with PD at different ages of onset. We included 22 patients; among them were 10 who had early-onset PD (EOPD) and 12 had late-onset PD (LOPD) and 10 young healthy controls (YHCs) and 8 elder HCs (EHCs). Mass cytometry staining technology was used to perform accurate immunotyping of cell populations in the peripheral blood. Motor symptoms and cognitive function were assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) III score and Mini-mental State Examination (MMSE) score, respectively. T test and ANOVA statistical analysis were performed on the frequency of annotated cell population. Linear regression model was used to analyze the correlation between clusters and clinical symptoms. We characterized 60 cell clusters and discovered that the immune signature of PD consists of cluster changes, including decreased effector CD8+ T cells, lower cytotoxicity natural killer (NK) cells and increased activated monocytes in PD patients. In summary, we found that CD8+ T cells, NK cells, and monocytes were associated with PD. Furthermore, there may be some differences in the immune status of patients with EOPD and LOPD, suggesting differences in the pathogenesis between these groups.

Systematic analysis of PINK1 variants of unknown significance shows intact mitophagy function for most variants

Pathogenic variants in PINK1 cause early-onset Parkinson’s disease. Although many PINK1 variants have been reported, the clinical significance is uncertain for the majority of them. To gain insights into the consequences of PINK1 missense variants in a systematic manner, we selected 50 PINK1 missense variants from patient- and population-wide databases and systematically classified them using Sherloc, a comprehensive framework for variant interpretation based on ACMG-AMP guidelines. We then performed functional experiments, including mitophagy and Parkin recruitment assays, to assess the downstream consequences of PINK1 variants. Analysis of PINK1 missense variants based on Sherloc showed that the patient databases over-annotate variants as likely pathogenic. Furthermore, our study shows that pathogenic PINK1 variants are most often linked to a loss-of-function for mitophagy and Parkin recruitment, while this is not observed for variants of unknown significance. In addition to the Sherloc framework, the added layer of evidence of our functional tests suggests a reclassification of 9/50 missense variants. In conclusion, we suggest the assessment of multiple layers of evidence, including functional data on top of available clinical and population-based data, to support the clinical classification of a variant and show that the presence of a missense variant in PINK1 in a Parkinson’s disease case does not automatically imply pathogenicity.