GBA1 and The Immune System: A Potential Role in Parkinson’s Disease?

Al-Azzawi, Zaid A.M.; Arfaie, Saman; Gan‐Or, Ziv

doi:10.3233/jpd-223423

Cited by 5 publications

(7 citation statements)

References 98 publications

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“…Moreover, the decrease in the GCase activity caused by GBA pathogenic variants has been shown to produce an accumulation of GCase substrates, which at the same time impairs lysosomal function and possibly leads to a decrease degradation of pathogenic synuclein, among other substrates. Some studies have suggested that when lysosome is overburdened, lysosomal vesicle contents may be released to extracellular space, activating antigen presentation, and exacerbating inflammatory immune responses through neutrophils and chronic inflammation 19 , 50 , 51 . In addition, it has been reported that monocyte GCase activity is reduced in sPD 52 .…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, polymorphisms in the LRRK2 gene have been linked to inflammatory and infectious diseases 14 . On the other hand, several studies highlight a link between GBA gene and inflammation in PD 19 . Early studies identified increased plasma levels of inflammatory markers and cytokines in GBA -associated PD ( GBA -PD) compared to sporadic PD (sPD) patients and HCs 20 .…”

Section: Introductionmentioning

confidence: 99%

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Peripheral inflammatory immune response differs among sporadic and familial Parkinson’s disease

Muñoz‐Delgado

Macías‐García

Periñán

et al. 2023

npj Parkinsons Dis.

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Peripheral inflammatory immune responses are thought to play a major role in the pathogenesis of Parkinson’s disease (PD). The neutrophil-to-lymphocyte ratio (NLR), a biomarker of systemic inflammation, has been reported to be higher in patients with PD than in healthy controls (HCs). The present study was aimed at determining if the peripheral inflammatory immune response could be influenced by the genetic background of patients with PD. We included a discovery cohort with 222 patients with PD (132 sporadic PD, 44 LRRK2-associated PD (with p.G2019S and p.R1441G variants), and 46 GBA-associated PD), as well as 299 HCs. Demographic and clinical data were recorded. Leukocytes and their subpopulations, and the NLR were measured in peripheral blood. Multivariate lineal regression and post-hoc tests were applied to determine the differences among the groups. Subsequently, a replication study using the Parkinson’s Progression Markers Initiative cohort was performed which included 401 patients with PD (281 sPD patients, 66 LRRK2-PD patients, 54 GBA-PD patients) and a group of 174 HCs. Patients with sporadic PD and GBA-associated PD showed a significantly lower lymphocyte count, a non-significantly higher neutrophil count and a significantly higher NLR than HCs. The peripheral inflammatory immune response of patients with LRRK2-associated PD did not differ from HCs. Our study supports the involvement of a peripheral inflammatory immune response in the pathophysiology of sPD and GBA-associated PD. However, this inflammatory response was not found in LRRK2-associated PD, probably reflecting different pathogenic inflammatory mechanisms.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Peripheral inflammatory immune response differs among sporadic and familial Parkinson’s disease

Muñoz‐Delgado

Macías‐García

Periñán

et al. 2023

npj Parkinsons Dis.

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“…Bioinformatic analysis utilizing gene expression and protein data have further corroborated shared genetic risk variants and molecular pathways [2]. Glucocerebrosidase (GBA) mutations which are found in 5-20% of PD patients worldwide have been implicated in aberrant immune responses (such as microglia-mediated antioxidant and protective response in neurons) [3]. There have been data to suggest neuroinflammation and peripheral immune changes in patients with isolated REM sleep behaviour disorder and asymptomatic carriers of GBA or LRRK2 gene mutations (the prodromal disease stage) [4].…”

mentioning

confidence: 99%

“…PD is influenced by many factors including a mix of immunogenetics and the environment, such as infection history. In recent years, increasing evidence suggests an association with autoimmune conditions, with the involvement of the immune system or its aberrant responses in patients and various experimental models [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. In this special issue, our authors highlight the latest research breakthroughs on the links between immune activation and neuroinflammation and PD, and discuss the challenges and novel therapeutic strategies targeting the immune system ISSN 1877-7171/$35.00 © 2022 -IOS Press.…”

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confidence: 99%

“…In summary, multiple independent studies in clinical and pre-clinical models have provided corroborative evidence of the involvement of central and peripheral immune and inflammatory processes in PD [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Our knowledge of how the immune system contributes to PD pathogenesis is constantly evolving with increasing evidence for a role of several genes and susceptibility loci [1,2].…”

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confidence: 99%

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Linking Immune Activation and Parkinson’s Disease

Bloem

Brundin

Tan

et al. 2022

JPD

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Longitudinal immunophenotyping to track motor progression in Parkinson’s Associated with a TH mutation

Gopinath,

Ramirez-Zamora,

Franks

et al. 2024

Preprint

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Background and Objectives: PD is the second most common neurodegenerative disorder and the fastest growing. Genetic factors account for ∼15% of cases. Despite some consistency in symptoms across idiopathic and genetic PD cases, tracking progression and treatment response remains an important challenge especially in the development of new therapies. There have been many traditional approaches to tracking including DaTscan imaging, cardiac 123I-MIBG scintigraphy, MRI, CSF analysis, and following clinical symptom progression. Methods: Our previous work showed that peripheral blood mononuclear cells (PBMCs) expressing dopamine transporter (DAT) and tyrosine hydroxylase (TH) in PD patients may correlate with disease progression and with the response to treatment with levodopa. We describe a single case longitudinal follow up of a 40-45-year-old woman with PD who carried a heterozygous TH mutation. We assessed her clinical features over 18 months with DaT scans and immunophenotyping of her PBMCs. Her data were compared with idiopathic PD (n=130 subjects, both sexes) and healthy controls (n=80, age/sex matched). Results: The results revealed a rise in DAT+ immune cells which occurred coincident to documented worsening of her UPDRS-III motor scores. Unlike idiopathic PD patients, following levodopa therapy, the TH+ immune cell levels remained elevated, despite UPDRS-III score improvement. Discussion: The longitudinal immunophenotyping in this PD patient with a TH mutation suggested that DAT+ and TH+ PBMCs could be candidate biomarkers for PD progression and possibly treatment effectiveness. This study provides proof of concept to explore this approach to investigate immunophenotyping in PD progression.

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GBA1 and The Immune System: A Potential Role in Parkinson’s Disease?

Cited by 5 publications

References 98 publications

Peripheral inflammatory immune response differs among sporadic and familial Parkinson’s disease

Peripheral inflammatory immune response differs among sporadic and familial Parkinson’s disease

Linking Immune Activation and Parkinson’s Disease

Longitudinal immunophenotyping to track motor progression in Parkinson’s Associated with a TH mutation

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