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α‐Synuclein accumulation and pathology in Parkinson's disease typically display a caudo‐rostral pattern of progression, involving neuronal nuclei in the medulla oblongata at the earliest stages. In this study, selective expression and accumulation of human α‐synuclein within medullary neurons was achieved via retrograde transport of adeno‐associated viral vectors unilaterally injected into the vagus nerve in the rat neck. The exogenous protein progressively spread toward more rostral brain regions where it could be detected within axonal projections. Propagation to the pons, midbrain and forebrain followed a stereotypical pattern of topographical distribution. It affected areas such as the coeruleus–subcoeruleus complex, dorsal raphae, hypothalamus and amygdala ipsilateral and, to a lesser extent, contralateral to the injection side. Spreading was accompanied by evidence of neuritic pathology in the form of axonal varicosities intensely immunoreactive for human α‐synuclein and containing Thioflavin‐S‐positive fibrils. Thus, overexpression of human α‐synuclein in the lower brainstem is sufficient to induce its long‐distance caudo‐rostral propagation, recapitulating features of Parkinson's disease and mechanisms of disease progression. Graphical Abstract α‐synuclein lesions spreading in the brain is characteristic of Parkinson's disease and used to stage the disease severity. Here, a new rat model can explain the caudo‐rostral pattern of disease progression providing insights into PD pathogenesis.

Age-related increases in monoamine oxidase B (MAO-B) may contribute to neurodegeneration associated with Parkinson's disease (PD). The MAO-B inhibitor deprenyl, a long-standing antiparkinsonian therapy, is currently used clinically in concert with the dopamine precursor L-DOPA. Clinical studies suggesting that deprenyl treatment alone is not protective against PD associated mortality were targeted to symptomatic patients. However, dopamine loss is at least 60% by the time PD is symptomatically detectable, therefore lack of effect of MAO-B inhibition in these patients does not negate a role for MAO-B in pre-symptomatic dopaminergic loss. In order to directly evaluate the role of age-related elevations in astroglial MAO-B in the early initiation or progression of PD, we created genetically engineered transgenic mice in which MAO-B levels could be specifically induced within astroglia in adult animals. Elevated astrocytic MAO-B mimicking age related increase resulted in specific, selective and progressive loss of dopaminergic neurons in the substantia nigra (SN), the same subset of neurons primarily impacted in the human condition. This was accompanied by other PD-related alterations including selective decreases in mitochondrial complex I activity and increased mitochondrial oxidative stress. Along with a global astrogliosis, we observed local microglial activation within the SN. These pathologies correlated with decreased locomotor activity. Importantly, these events occurred even in the absence of the PD-inducing neurotoxin MPTP. Our data demonstrates that elevation of murine astrocytic MAO-B by itself can induce several phenotypes of PD, signifying that MAO-B could be directly involved in multiple aspects of disease neuropathology. Mechanistically this may involve increases in membrane permeant H(2)O(2) which can oxidize dopamine within dopaminergic neurons to dopaminochrome which, via interaction with mitochondrial complex I, can result in increased mitochondrial superoxide. Our inducible astrocytic MAO-B transgenic provides a novel model for exploring pathways involved in initiation and progression of several key features associated with PD pathology and for therapeutic drug testing.

Background Cucurbita pepo is highly susceptible to Zucchini yellow mosaic virus (ZYMV) and the resistance found in several wild species cannot be considered as complete or broad-spectrum resistance. In this study, a source of tolerance introgressed in C. pepo (381e) from C. moschata, in True French (TF) background, was investigated 12 days post-inoculation (DPI) at transcriptomic and genomic levels. Results The comparative RNA-sequencing (RNA-Seq) of TF (susceptible to ZYMV) and 381e (tolerant to ZYMV) allowed the evaluation of about 33,000 expressed transcripts and the identification of 146 differentially expressed genes (DEGs) in 381e, mainly involved in photosynthesis, transcription, cytoskeleton organization and callose synthesis. By contrast, the susceptible cultivar TF triggered oxidative processes related to response to biotic stimulus and activated key regulators of plant virus intercellular movement. In addition, the discovery of variants located in transcripts allowed the identification of two chromosome regions rich in Single Nucleotide Polymorphisms (SNPs), putatively introgressed from C. moschata, containing genes exclusively expressed in 381e. Conclusion 381e transcriptome analysis confirmed a global improvement of plant fitness by reducing the virus titer and movement. Furthermore, genes implicated in ZYMV tolerance in C. moschata introgressed regions were detected. Our work provides new insight into the plant virus recovery process and a better understanding of the molecular basis of 381e tolerance.

Propagation of α-synuclein aggregates has been suggested as a contributing factor in Parkinson’s disease (PD) progression. However, the molecular mechanisms underlying α-synuclein aggregation are not fully understood. Here, we demonstrate in cell culture, nematode, and rodent models of PD that leucine-rich repeat kinase 2 (LRRK2), a PD-linked kinase, modulates α-synuclein propagation in a kinase activity-dependent manner. The PD-linked G2019S mutation in LRRK2, which increases kinase activity, enhances propagation efficiency. Furthermore, we show that the role of LRRK2 in α-synuclein propagation is mediated by RAB35 phosphorylation. Constitutive activation of RAB35 overrides the reduced α-synuclein propagation phenotype in lrk-1 mutant C. elegans . Finally, in a mouse model of synucleinopathy, administration of an LRRK2 kinase inhibitor reduced α-synuclein aggregation via enhanced interaction of α-synuclein with the lysosomal degradation pathway. These results suggest that LRRK2-mediated RAB35 phosphorylation is a potential therapeutic target for modifying disease progression. Mutations in LRRK2 kinase are associated with Parkinson’s disease. Here the authors show that LRRK2 modulates propagation of α-synuclein, using rodent and C. elegans models, and show that this is dependent on phosphorylation of one of its substrates, RAB35.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron degeneration and α-synuclein (aSyn) accumulation. Environmental factors play a significant role in PD progression, highlighting the potential of non-pharmacological interventions. This study investigates the therapeutic effects of intermittent fasting (IF) in an rAAV-aSyn mouse model of PD. IF, initiated four weeks post-induction of aSyn pathology, improved motor function and reduced dopaminergic neuron and axon terminal degeneration. Additionally, IF preserved dopamine levels and synaptic integrity in the striatum. Mechanistically, IF enhanced autophagic activity, promoting phosphorylated-aSyn clearance and reducing its accumulation in insoluble brain fractions. Transcriptome analysis revealed IF-induced modulation of inflammation-related genes and microglial activation. Validation in primary cultures confirmed that autophagy activation and inflammatory modulators (CCL17, IL-36RN) mitigate aSyn pathology. These findings suggest that IF exerts neuroprotective effects, supporting further exploration of IF and IF-mimicking therapies as potential PD treatments. Comparison of intermittent fasting (IF) to a standard diet in a mouse model of Parkinson’s disease demonstrated that IF improved movement, protected dopamine neurons, and enhanced the brain’s clearance process, reducing toxic protein buildup and inflammation.

Background Homozygotic mutations in the GBA gene cause Gaucher’s disease; moreover, both patients and heterozygotic carriers have been associated with 20- to 30-fold increased risk of developing Parkinson’s disease. In homozygosis, these mutations impair the activity of β-glucocerebrosidase, the enzyme encoded by GBA, and generate a lysosomal disorder in macrophages, which changes morphology towards an engorged phenotype, considered the hallmark of Gaucher’s disease. Notwithstanding the key role of macrophages in this disease, most of the effects in the brain have been attributed to the β-glucocerebrosidase deficit in neurons, while a microglial phenotype for these mutations has never been reported. Methods We applied the bioluminescence imaging technology, immunohistochemistry and gene expression analysis to investigate the consequences of microglial β-glucocerebrosidase inhibition in the brain of reporter mice, in primary neuron/microglia cocultures and in cell lines. The use of primary cells from reporter mice allowed for the first time, to discriminate in cocultures neuronal from microglial responses consequent to the β-glucocerebrosidase inhibition; results were finally confirmed by pharmacological depletion of microglia from the brain of mice. Results Our data demonstrate the existence of a novel neuroprotective mechanism mediated by a direct microglia-to-neuron contact supported by functional actin structures. This cellular contact stimulates the nuclear factor erythroid 2-related factor 2 activity in neurons, a key signal involved in drug detoxification, redox balance, metabolism, autophagy, lysosomal biogenesis, mitochondrial dysfunctions, and neuroinflammation. The central role played by microglia in this neuronal response in vivo was proven by depletion of the lineage in the brain of reporter mice. Pharmacological inhibition of microglial β-glucocerebrosidase was proven to induce morphological changes, to turn on an anti-inflammatory/repairing pathway, and to hinder the microglia ability to activate the nuclear factor erythroid 2-related factor 2 response, thus increasing the neuronal susceptibility to neurotoxins. Conclusion This mechanism provides a possible explanation for the increased risk of neurodegeneration observed in carriers of GBA mutations and suggest novel therapeutic strategies designed to revert the microglial phenotype associated with β-glucocerebrosidase inhibition, aimed at resetting the protective microglia-to-neuron communication.

The clinical progression of neurodegenerative diseases correlates with the spread of proteinopathy in the brain. The current understanding of the mechanism of proteinopathy spread is far from complete. Here, we propose that inflammation is fundamental to proteinopathy spread. A sequence variant of α-synuclein (V40G) was much less capable of fibril formation than wild-type α-synuclein (WT-syn) and, when mixed with WT-syn, interfered with its fibrillation. However, when V40G was injected intracerebrally into mice, it induced aggregate spreading even more effectively than WT-syn. Aggregate spreading was preceded by sustained microgliosis and inflammatory responses, which were more robust with V40G than with WT-syn. Oral administration of an anti-inflammatory agent suppressed aggregate spreading, inflammation, and behavioral deficits in mice. Furthermore, exposure of cells to inflammatory cytokines increased the cell-to-cell propagation of α-synuclein. These results suggest that the inflammatory microenvironment is the major driver of the spread of synucleinopathy in the brain.Neurodegenerative diseases: inflammation drives spread of protein aggregatesThe growth of protein aggregates that cause neurodegenerative diseases is greatly accelerated by inflammatory immune responses, researchers in Korea and Germany have shown. Diseases such as Alzheimer’s and Parkinson’s show unique patterns of aggregates, which spread via the cell-to-cell transfer of proteins such as α-synuclein. To investigate other factors that may contribute to aggregation, Seung-Jae Lee at Seoul National University, South Korea, and co-workers developed a variant of α-synuclein called V40G, which was largely incapable of forming aggregates in vitro. However, when the team injected V40G into mice, it induced aggregate spreading even more effectively than the wild-type α-synuclein, along with a sustained inflammatory response. Adding an anti-inflammatory agent suppressed the spreading of aggregates and reduced behavioural symptoms in the mice, suggesting that inflammation is a major driver of pathogenic protein aggregation in the brain.

The protein alpha-synuclein is involved in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. Its toxic potential appears to be enhanced by increased protein expression, providing a compelling rationale for therapeutic strategies aimed at reducing neuronal alpha-synuclein burden. Here, feasibility and safety of alpha-synuclein suppression were evaluated by treating monkeys with small interfering RNA (siRNA) directed against alpha-synuclein. The siRNA molecule was chemically modified to prevent degradation by exo- and endonucleases and directly infused into the left substantia nigra. Results compared levels of alpha-synuclein mRNA and protein in the infused (left) vs. untreated (right) hemisphere and revealed a significant 40-50% suppression of alpha-synuclein expression. These findings could not be attributable to non-specific effects of siRNA infusion since treatment of a separate set of animals with luciferase-targeting siRNA produced no changes in alpha-synuclein. Infusion with alpha-synuclein siRNA, while lowering alpha-synuclein expression, had no overt adverse consequences. In particular, it did not cause tissue inflammation and did not change (i) the number and phenotype of nigral dopaminergic neurons, and (ii) the concentrations of striatal dopamine and its metabolites. The data represent the first evidence of successful anti-alpha-synuclein intervention in the primate substantia nigra and support further development of RNA interference-based therapeutics.

Recent epidemiological and experimental studies have renewed interest in the hypothesis that the environment has a role in the pathogenesis of Parkinson's disease (PD). Epidemiological studies have identified protective associations (eg, smoking) as well as adverse risk factors (eg, pesticide exposure) for PD. The concordance rate of PD in pairs of dizygotic twins is similar to that in pairs of monozygotic twins, supporting a role of non-genetic risk factors. New models of selective nigrostriatal damage—such as neurotoxicity induced by rotenone or paraquat—have emphasised that environmental agents may contribute to the neurodegenerative process in PD. Toxins interact, in vitro and in vivo, with α—synuclein, an endogenous protein that is implicated in pathology of PD. Similarities between clinical and experimental findings, such as the role of pesticide exposure as a potential environmental risk factor, highlight the importance of a multidisciplinary approach to the aetiology of PD.

Mutations in the GBA gene, which reduce β-glucocerebrosidase (GCase) activity, represent the most significant genetic risk factor for Parkinson’s disease (PD). Decreased GCase activity has also been observed in sporadic PD cases, supporting a broader role for GCase in the poorly understood mechanisms underlying PD etiopathogenesis. While most studies on the relationship between GBA mutations and PD have focused on neurons, evidence suggests that PD pathology promoted by GCase deficiency involves other cell types and, in particular, interactions between neuronal and glial cells. Here, we identify microglia as primary players undergoing significant alterations at early stages of the pathological processes triggered by a GCase impairment. Using both pharmacological and genetic mouse models of GCase deficiency, we observed microglial morphological, transcriptional and metabolic changes. Interestingly, these changes were associated with a cell-specific, significant reduction of microglial ATP levels. When microglial ATP depletion was reproduced in an in vitro system of co-cultured microglial and neuronal cells, the neuroprotective properties of microglia were compromised, resulting in reduced cytoprotective and detoxifying pathways in neurons. These findings underscore the role of microglia in PD pathogenesis and point to a pathogenetic mechanism by which microglial metabolic disturbances leading to ATP depletion enhance neuronal vulnerability to injury and neurodegeneration. This mechanism could be targeted for therapeutic intervention aimed at mitigating PD risk and counteracting the development of PD pathology.