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  • Endogenous coimmunoprecipitation

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    Protocol used for immunoprecipitation of HSP60 and LONP1 in HEK cells to show the interaction with V5-Flag-tagged WT-GCase

  • Neuromelanin staining (Fontana-Masson staining)+ TH-DAB staining on midbrain organoids

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    Neuromelanin staining (Fontana-Masson staining)+ TH-DAB staining on midbrain organoids

  • Who is at Risk of Parkinson Disease? Refining the Preclinical Phase of GBA1 and LRRK2 Variant Carriers: a Clinical, Biochemical, and Imaging Approach

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    Purpose of Review Genetic variants in GBA1 and LRRK2 genes are the commonest genetic risk factor for Parkinson disease (PD); however, the preclinical profile of GBA1 and LRRK2 variant carriers who will develop PD is unclear. This review aims to highlight the more sensitive markers that can stratify PD risk in non-manifesting GBA1 and LRRK2 variant carriers. Recent Findings Several case–control and a few longitudinal studies evaluated clinical, biochemical, and neuroimaging markers within cohorts of non-manifesting carriers of GBA1 and LRRK2 variants. Summary Despite similar levels of penetrance of PD in GBA1 and LRRK2 variant carriers (10–30%), these individuals have distinct preclinical profiles. GBA1 variant carriers at higher risk of PD can present with prodromal symptoms suggestive of PD (hyposmia), display increased α-synuclein levels in peripheral blood mononuclear cells, and show dopamine transporter abnormalities. LRRK2 variant carriers at higher risk of PD might show subtle motor abnormalities, but no prodromal symptoms, higher exposure to some environmental factors (non-steroid anti-inflammatory drugs), and peripheral inflammatory profile. This information will help clinicians tailor appropriate screening tests and counseling and facilitate researchers in the development of predictive markers, disease-modifying treatments, and selection of healthy individuals who might benefit from preventive interventions.

  • Differential response of α-synuclein expression to bacterial ligands and metabolites in mouse enteroendocrine cells

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    Dataset for manuscript " α-synuclein expression in response to bacterial ligands and metabolites in gut enteroendocrine cells". Tabs in excel file are title with the figure number.

  • LRRK2 regulates the activation of the unfolded protein response and antigen presentation in macrophages during inflammation

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    Absence of PINK1 leads to MitAP over-activation engaging autoimmune mechanisms. This pathway is induced by TLR4, cGAS-STING, and UPR activation in response to inflammatory signals. LRRK2 and STING regulate transition from innate to adaptive immunity

  • Genome-wide determinants of mortality and motor progression in Parkinson’s disease

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    The authors examined the impact of gene variants on mortality and cognitive impairment in PD. Only the non-Gaucher disease causing GBA PD risk variant E326K, of the known PD risk variants, was associated with progression in PD.

  • Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism – ASAP protocol collection

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    Collection of protocols of Deleidi Lab used in the publication: "Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism."

  • Central and Peripheral Inflammation: Connecting the Immune Responses of Parkinson’s Disease

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    Authors highlight the important work being done that implicates central and peripheral inflammation in playing a role in PD.

  • Neuronal hyperactivity-induced oxidant stress promotes in vivo α-synuclein brain spreading

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    Interneuronal transfer and brain spreading of pathogenic proteins are features of neurodegenerative diseases. Pathophysiological conditions and mechanisms affecting this spreading remain poorly understood. This study investigated the relationship between neuronal activity and interneuronal transfer of α-synuclein, a Parkinson-associated protein, and elucidated mechanisms underlying this relationship. In a mouse model of α-synuclein brain spreading, hyperactivity augmented and hypoactivity attenuated protein transfer. Important features of neuronal hyperactivity reported here were an exacerbation of oxidative and nitrative reactions, pronounced accumulation of nitrated α-synuclein, and increased protein aggregation. Data also pointed to mitochondria as key targets and likely sources of reactive oxygen and nitrogen species within hyperactive neurons. Rescue experiments designed to counteract the increased burden of reactive oxygen species reversed hyperactivity-induced α-synuclein nitration, aggregation, and interneuronal transfer, providing first evidence of a causal link between these pathological effects of neuronal stimulation and indicating a mechanistic role of oxidant stress in hyperactivity-induced α-synuclein spreading.

  • LRRK2-G2019S Synergizes with Ageing and Low-Grade Inflammation to Promote Gut and Peripheral Immune Cell Activation that Precede Nigrostriatal Degeneration

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    Background Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of familial Parkinson’s disease (PD). The incomplete penetrance of LRRK2 mutations suggest that additional hits are required for disease onset. We hypothesized that chronic low-grade inflammation interacts with LRRK2 G2019S, the most frequent PD-associated mutation, to activate peripheral and central immune reactions and drive age-dependent neurodegeneration. Methods and Results We exposed wild-type and LRRK2 G2019S mice to a low chronic dose of lipopolysaccharide, and we performed a longitudinal analysis of central and peripheral immune reactions and neurodegeneration. Low-dose inflammation triggered nigrostriatal degeneration, macrophage/monocyte brain infiltration, and astro-/microgliosis. LRRK2 G2019S mice showed an early dysregulation of peripheral cytokines, increased CD4+ T-cell infiltration and α-synuclein aggregation in the colon. Interestingly, peripheral immune activation and colonic α-synuclein aggregation precede astro-/microgliosis and neurodegeneration. Conclusions Our study suggests an early role of the peripheral immune system and the gut in LRRK2 PD and provides a novel model to study early therapeutic immune targets and biomarkers.

  • Protocols for “Synaptotagmin-1-dependent phasic axonal dopamine release is dispensable for basic motor behaviors in mice”

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    This is a collection of protocols for the manuscript "Synaptotagmin-1-dependent phasic axonal dopamine release is dispensable for basic motor behaviors in mice"

  • The remote assessment of parkinsonism supporting the ongoing development of interventions in Gaucher disease

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    Mutations in GBA which are causative of Gaucher disease in their biallelic form, are the most common genetic risk factor for Parkinson's disease (PD). The diagnosis of PD relies upon clinically defined motor features which appear after irreversible neurodegeneration. Prodromal symptoms of PD may provide a means to predict latent pathology, years before the onset of motor features. Previous work has reported prodromal features of PD in GBA mutation carriers, however this has been insufficiently sensitive to identify those that will develop PD. The Remote Assessment of Parkinsonism Supporting Ongoing Development of Interventions in Gaucher Disease (RAPSODI GD) study assesses a large cohort of GBA mutation carriers, to aid development of procedures for earlier diagnosis of PD.

  • Striatal dopamine measurement through HPLC

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    Protocol for striatal dopamine measurement in mouse brain

  • Stereotaxic Injections

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    Stereotaxic injections for Conserved and cell type-specific transcriptional responses to IFN-γ in the ventral midbrain.

  • Code for integrated multi-cohort analysis of the Parkinson’s disease gut metagenome

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    Detailed scripts to reproduce all analysis and data visualization for the paper "Integrated multi-cohort analysis of the Parkinson's disease gut metagenome."

  • Transcriptional analysis of peripheral memory T cells reveals Parkinson’s disease-specific gene signatures–Gene Validation FCS

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    FCS files corresponding to the gene validation experiment described in "Transcriptional analysis of peripheral memory T cells reveals Parkinson’s disease-specific gene signatures"

  • Transcriptional analysis of peripheral memory T cells reveals Parkinson’s disease-specific gene signatures–Cell Surface FCS

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    FCS files corresponding to the cell surface experiment described in "Transcriptional analysis of peripheral memory T cells reveals Parkinson’s disease-specific gene signatures"

  • Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease

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    Border-associated macrophages (BAMs) are crucial in Parkinson's disease pathogenesis by initiating neuroinflammation, highlighting a potential target for therapeutic intervention.

  • Glucocerebrosidase 1 and leucine-rich repeat kinase 2 in Parkinson disease and interplay between the two genes

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    Review: This review focuses on the endolysosomal pathway roles of GBA and LRRK2, highlighting the role and activity of Rab GTPases as LRRK2 substrates.

  • Mitochondrial Antigen Presentation in RAW macrophages

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    This protocol details methods for 3-day Mitochondrial Antigen Presentation Assay in a murine macrophage cell line (RAW) that expresses a glycoprotein B (gB) of herpes simplex virus 1 (HSV1) targeted to the mitochondrial matrix (mito-gB). A gB-specific CD8+ T cell hybridoma recognizing the gB498–505peptide loaded on MHC class I molecules is also used to monitor antigen presentation through a beta-galactosidase assay kit.

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