Parkinson’s disease is a common and debilitating disorder. The best-known features are resting tremor, rigidity, and slowness, but recently a fuller picture of the associated complications has ...emerged, encompassing autonomic symptoms, sleep disorders, and cognitive impairment. A common experience of persons with Parkinson’s disease is the relentless progression of symptoms and the resultant disability. The development of neuroprotective treatments, capable of slowing, stopping, or reversing neurodegeneration, has long been a priority in the field.
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Indeed, James Parkinson expressed his optimism for such a treatment in his 1817 publication,
An Essay on the Shaking Palsy
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noting that although the nature of . . .
Increasing evidence points to inflammation as a chief mediator of Parkinson's disease (PD), a progressive neurodegenerative disorder characterized by loss of dopamine neurons in the substantia nigra ...pars compacta (SNpc) and widespread aggregates of the protein α-synuclein (α-syn). Recently, microRNAs, small, noncoding RNAs involved in regulating gene expression at the posttranscriptional level, have been recognized as important regulators of the inflammatory environment. Using an array approach, we found significant upregulation of microRNA-155 (miR-155) in an in vivo model of PD produced by adeno-associated-virus-mediated expression of α-syn. Using a mouse with a complete deletion of miR-155, we found that loss of miR-155 reduced proinflammatory responses to α-syn and blocked α-syn-induced neurodegeneration. In primary microglia from miR-155(-/-) mice, we observed a markedly reduced inflammatory response to α-syn fibrils, with attenuation of major histocompatibility complex class II (MHCII) and proinflammatory inducible nitric oxide synthase expression. Treatment of these microglia with a synthetic mimic of miR-155 restored the inflammatory response to α-syn fibrils. Our results suggest that miR-155 has a central role in the inflammatory response to α-syn in the brain and in α-syn-related neurodegeneration. These effects are at least in part due to a direct role of miR-155 on the microglial response to α-syn. These data implicate miR-155 as a potential therapeutic target for regulating the inflammatory response in PD.
Parkinson's disease (PD) may start in the gut and spread to the brain. To investigate the role of gut microbiome, we conducted a large-scale study, at high taxonomic resolution, using uniform ...standardized methods from start to end. We enrolled 490 PD and 234 control individuals, conducted deep shotgun sequencing of fecal DNA, followed by metagenome-wide association studies requiring significance by two methods (ANCOM-BC and MaAsLin2) to declare disease association, network analysis to identify polymicrobial clusters, and functional profiling. Here we show that over 30% of species, genes and pathways tested have altered abundances in PD, depicting a widespread dysbiosis. PD-associated species form polymicrobial clusters that grow or shrink together, and some compete. PD microbiome is disease permissive, evidenced by overabundance of pathogens and immunogenic components, dysregulated neuroactive signaling, preponderance of molecules that induce alpha-synuclein pathology, and over-production of toxicants; with the reduction in anti-inflammatory and neuroprotective factors limiting the capacity to recover. We validate, in human PD, findings that were observed in experimental models; reconcile and resolve human PD microbiome literature; and provide a broad foundation with a wealth of concrete testable hypotheses to discern the role of the gut microbiome in PD.
Dystonia and levodopa-induced dyskinesia (LID) are both hyperkinetic movement disorders. Dystonia arises most often spontaneously, although it may be seen after stroke, injury, or as a result of ...genetic causes. LID is associated with Parkinson's disease (PD), emerging as a consequence of chronic therapy with levodopa, and may be either dystonic or choreiform. LID and dystonia share important phenomenological properties and mechanisms. Both LID and dystonia are generated by an integrated circuit involving the cortex, basal ganglia, thalamus and cerebellum. They also share dysregulation of striatal cholinergic signaling and abnormalities of striatal synaptic plasticity. The long duration nature of both LID and dystonia suggests that there may be underlying epigenetic dysregulation as a proximate cause. While both may improve after interventions such as deep brain stimulation (DBS), neither currently has a satisfactory medical therapy, and many people are disabled by the symptoms of dystonia and LID. Further study of the fundamental mechanisms connecting these two disorders may lead to novel approaches to treatment or prevention.
•Levodopa-induced dyskinesia (LID) and dystonia share important phenomenological properties and mechanisms.•Both LID and dystonia are generated by an integrated circuit involving the cortex, basal ganglia, thalamus and cerebellum.•LID and dystonia share dysregulation of striatal cholinergic signaling, and abnormalities of striatal synaptic plasticity.•The long duration nature of both LID and dystonia suggests that there may be underlying epigenetic dysregulation as a proximate cause.
Abstract Dystonia is a clinical syndrome with sustained muscle contraction, twisting, and abnormal postures. A number of different genetic forms have been defined, but most cases are sporadic in ...nature and of uncertain cause. Relatively few cases of dystonia have been studied pathologically. In primary dystonias, where dystonia is the main symptom, most reports describe little or no detectable neuropathology, although changes in brainstem neurons have been described in some cases. Secondary dystonias are associated with degenerative or destructive diseases of the nervous system; the pathology may be located in the basal ganglia, but in some cases the primary pathological changes are found in the cerebellum or cerebellar outflow pathways, suggesting that both regions may be involved in the pathogenesis of dystonic symptoms. Overall the number of well-documented pathological cases available for study is few, and there is an urgent need for additional postmortem studies. This article is part of a Special Issue entitled “Advances in dystonia”.
A diagnosis of motor Parkinson's disease (PD) is preceded by a prolonged premotor phase with accumulating neuronal damage. Here we examined the temporal relation between α-synuclein (α-syn) T cell ...reactivity and PD. A longitudinal case study revealed that elevated α-syn-specific T cell responses were detected prior to the diagnosis of motor PD, and declined after. The relationship between T cell reactivity and early PD in two independent cohorts showed that α-syn-specific T cell responses were highest shortly after diagnosis of motor PD and then decreased. Additional analysis revealed significant association of α-syn-specific T cell responses with age and lower levodopa equivalent dose. These results confirm the presence of α-syn-reactive T cells in PD and show that they are most abundant immediately after diagnosis of motor PD. These cells may be present years before the diagnosis of motor PD, suggesting avenues of investigation into PD pathogenesis and potential early diagnosis.
Abstract
α-Synuclein, a key pathological component of Parkinson's disease, has been implicated in the activation of the innate and adaptive immune system. This immune activation includes ...microgliosis, increased inflammatory cytokines, and the infiltration of T cells into the CNS. More recently, peripherally circulating CD4 and CD8 T cells derived from individuals with Parkinson’s disease have been shown to produce Th1/Th2 cytokines in response to α-synuclein, suggesting there may be a chronic memory T cell response present in Parkinson’s disease. To understand the potential effects of these α-syn associated T cell responses we used an α-synuclein overexpression mouse model, T cell-deficient mice, and a combination of immunohistochemistry and flow cytometry. In this study, we found that α-synuclein overexpression in the midbrain of mice leads to the upregulation of the major histocompatibility complex II (MHCII) protein on CNS myeloid cells as well as the infiltration of IFNγ producing CD4 and CD8 T cells into the CNS. Interestingly, genetic deletion of TCRβ or CD4, as well as the use of the immunosuppressive drug fingolimod, were able to reduce the CNS myeloid MHCII response to α-synuclein. Furthermore, we observed that CD4-deficient mice were protected from the dopaminergic cell loss observed due to α-syn overexpression. These results suggest that T cell responses associated with α-synuclein pathology may be damaging to key areas of the CNS in Parkinson’s disease and that targeting these T cell responses could be an avenue for disease modifying treatments.
The protein alpha-synuclein (α-SYN), which is found in the Lewy bodies of dopamine-producing (DA) neurons in the substantia nigra (SN), has an important role in the pathogenesis of Parkinson's ...disease (PD). Previous studies have shown that neuroinflammation plays a key role in PD pathogenesis. In an AAV-synuclein mouse model of PD, we have found that over-abundance of α-SYN triggers the expression of NF-κB p65, and leads to microglial activation and DA neurodegeneration. We also have observed that Fcγ receptors (FcγR), proteins present on the surface of microglia that bind immunoglobulin G (IgG) and other ligands, are key modulators of α-SYN-induced neurodegeneration.
In order to study the role of FcγRs in the interactions of α-SYN and microglia, we treated the primary microglial cultures from wild-type (WT) and FcγR-/- mice with aggregated human α-SYN in vitro.
Using immunocytochemistry, we found that α-SYN was taken up by both WT and FcγR-/- microglia, however, their patterns of internalization were different, with aggregation in autophagosomes in WT cells and more diffuse localization in FcγR-/- microglia. In WT microglia, α-SYN induced the nuclear accumulation of NF-κB p65 protein and downstream chemokine expression while in FcγR-/- mouse microglia, α-SYN failed to trigger the enhancement of nuclear NF-κB p65, and the pro-inflammatory signaling was reduced.
Our results suggest that α-SYN can interact directly with microglia and can be internalized and trafficked to autophagosomes. FcγRs mediate this interaction, and in the absence of the gamma chain, there is altered intracellular trafficking and attenuation of pro-inflammatory NF-κB signaling. Therefore, blocking either FcγR signaling or downstream NF-κB activation may be viable therapeutic strategies in PD.
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