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The immune system is increasingly recognized as playing an important role in the pathogenesis of the neurodegenerative movement disorder Parkinson’s disease (PD). In particular, key PD risk genes LRRK2 (which encodes leucine-rich repeat kinase 2) and GBA1 (which encodes glucocerebrosidase) are highly expressed in monocytes and implicated in the regulation of immune inflammatory pathways and lysosomal function. While preclinical studies demonstrate that missense mutations in LRRK2 and GBA1 can modulate the response to inflammatory stimuli, studies in primary immune cells from PD patients harboring these mutations are few. Therefore, peripheral blood mononuclear cells were obtained from idiopathic PD patients, ( n  = 42), as well as PD patients with GBA1 ( n  = 15) and LRRK2 ( n  = 13) mutations, and neurologically normal controls ( n  = 36). Cells were stimulated with interferon gamma, which strongly induces expression of the LRRK2 protein, and treated with and without the LRRK2 kinase inhibitor MLi-2. Live and fixed cell flow cytometry panels were used to measure the activities of LRRK2 and glucocerebrosidase, as well as cathepsin activity and the expression of the human leukocyte antigen receptor (HLA-DR) in classical, intermediate, and non-classical monocytes. Interferon gamma stimulation had marked effects on LRRK2 levels and phosphorylation of the LRRK2 substrate Rab10, as well as effects on the expression of HLA-DR and cathepsin activity, with some mutation-specific and monocyte-type-specific outcomes. These results help to advance understanding of how risk genes may interact with immune stimuli in the context of PD.

Mounting data suggest an important role for the immune system in Parkinson’s disease (PD). Previous evidence of increased natural killer (NK) cell populations in PD suggests a potential role of NK cells in the pathogenesis of the disease. Previous studies have analyzed NK cell populations using aggregation by variable expression of CD56 and CD16. It remains unknown what differences may exist between NK cell subpopulations when stratified using more nuanced classification. Here, we profile NK cell subpopulations and elucidate the expressions of activating, NKG2D, inhibitory, NKG2A, and homing, CX3CR1, receptors on NK cell subpopulations in PD and healthy controls (HC). We analyzed cryopreserved PMBC samples using a 10-color flow cytometry panel to evaluate NK cell subpopulations in 31 individuals with sporadic PD and 27 HC participants. Here we identified significant differences in the CD56 dim NK subset that changes with disease severity in PD. Furthermore, the expressions of NKG2D in all three NK cell subsets were significantly elevated in PD patients compared to HC. Notably, NKG2A expression in the CD56 bright NK subset increased in PD patients with longer disease duration but there were no changes in CX3CR1. In summary, our data suggests that changes in NK cells may be influenced by the clinical severity and duration of PD.

Epitopes derived from two regions of α-synuclein elicit immune responses in patients with Parkinson’s disease, involving IL-5-secreting CD4 + T cells, as well as IFNγ-secreting CD8 + cytotoxic T cells. A possible immune component to Parkinson's disease Major pathological hallmarks of Parkinson's disease are the death of neurons in the substantia nigra, a region of the brain associated with movement, and the presence of intraneuronal aggregates of α-synuclein. Genetic studies associate Parkinson's disease with alleles of the major histocompatibility complex. David Sulzer and colleagues show here that a defined set of peptides derived from α-synuclein is able to elicit a specific immune response from T cells obtained from Parkinson's disease patients. This suggests that there may be an immune component to the origins of Parkinson's disease, involving CD4 + T cells as well as CD8 + cytotoxic T cells, which may explain the reported association of Parkinson's disease with alleles of the acquired immune system. Genetic studies have shown the association of Parkinson’s disease with alleles of the major histocompatibility complex 1 , 2 , 3 . Here we show that a defined set of peptides that are derived from α-synuclein, a protein aggregated in Parkinson’s disease 4 , act as antigenic epitopes displayed by these alleles and drive helper and cytotoxic T cell responses in patients with Parkinson’s disease. These responses may explain the association of Parkinson’s disease with specific major histocompatibility complex alleles.

Human microglial heterogeneity is only beginning to be appreciated at the molecular level. Here, we present a large, single-cell atlas of expression signatures from 441,088 live microglia broadly sampled across a diverse set of brain regions and neurodegenerative and neuroinflammatory diseases obtained from 161 donors sampled at autopsy or during a neurosurgical procedure. Using single-cell hierarchical Poisson factorization (scHPF), we derived a 23-factor model for continuous gene expression signatures across microglia which capture specific biological processes (e.g., metabolism, phagocytosis, antigen presentation, inflammatory signaling, disease-associated states). Using external datasets, we evaluated the aspects of microglial phenotypes that are encapsulated in various and microglia models and identified and replicated the role of two factors in human postmortem tissue of Alzheimer's disease (AD). Further, we derived a complex network of transcriptional regulators for all factors, including regulators of an AD-related factor enriched for the mouse disease-associated microglia 2 (DAM2) signature: , and . We replicated the role of these four regulators in the AD-related factor and then designed a multiplexed MERFISH panel to assess our microglial factors using spatial transcriptomics. We find that, unlike cells with high expression of the interferon-response factor, cells with high expression of the AD DAM2-like factor are widely distributed in neocortical tissue. We thus propose a novel analytic framework that provides a taxonomic approach for microglia that is more biologically interpretable and use it to uncover new therapeutic targets for AD.

The discovery that α-synuclein can be detected in peripheral tissues of patients with Parkinson's disease and other synucleinopathies spurred the development of biomarker assays, including the α-synuclein seed amplification assay for CSF and immunofluorescence detection of dermal phosphorylated-α-synuclein. These tools aim to identify pathological α-synuclein changes, even at the early stages of disease, with the goal of eventually enabling differentiation of Parkinson's disease from other neurodegenerative disorders, including tauopathies. α-synuclein biomarkers add a biological component to the traditional clinical diagnosis of Parkinson's disease, with potential for development of complementary clinical and pathobiological frameworks for Parkinson's disease and related movement disorders. However, use of existing α-synuclein biomarkers is restricted to research settings due to variable sensitivity and specificity, restricted availability of neuropathological data for validation, and scarcity of longitudinal studies. Addressing these limitations is crucial for advancing clinical and biological disease definitions, which will be essential for the development of disease-modifying therapies.

Mounting data suggest an important role for the immune system in Parkinson's disease (PD). Previous evidence of increased natural killer (NK) cell populations in PD suggests a potential role of NK cells in the pathogenesis of the disease. Previous studies have analyzed NK cell populations using aggregation by variable expression of CD56 and CD16. It remains unknown what differences may exist between NK cell subpopulations when stratified using more nuanced classification. Here, we profile NK cell subpopulations and elucidate the expressions of activating, NKG2D, inhibitory, NKG2A, and homing, CX3CR1, receptors on NK cell subpopulations in PD and healthy controls (HC). We analyzed cryopreserved PMBC samples using a 10-color flow cytometry panel to evaluate NK cell subpopulations in 31 individuals with sporadic PD and 27 HC participants. Here we identified significant differences in the CD56 NK subset that changes with disease severity in PD. Furthermore, the expressions of NKG2D in all three NK cell subsets were significantly elevated in PD patients compared to HC. Notably, NKG2A expression in the CD56 NK subset increased in PD patients with longer disease duration but there were no changes in CX3CR1. In summary, our data suggests that changes in NK cells may be influenced by the clinical severity and duration of PD.

Genetic studies associate Parkinson’s disease with alleles of the major histocompatibility complex1–3. We find that a defined set of peptides derived from α-synuclein, a protein aggregated in Parkinson’s disease4, act as antigenic epitopes displayed by these alleles and drive helper and cytotoxic T cell responses in Parkinson’s disease patients. These responses may explain the association of Parkinson’s disease with alleles of the acquired immune system.

Nature 546, 656–661 (2017); doi:10.1038/nature22815 In this Letter, owing to an error during the production process, two values in Table 1 were incorrect. The relative frequency for the DQB1*03:04 allele should have been ‘4.5’ rather than ‘0’, and the odds ratio for the DQB1*03:04 allele should have been ‘inf.’ rather than ‘11’. The original Letter has been corrected online.