Dataset Information

Transcriptome deregulation of peripheral monocytes and whole blood in GBA-related Parkinson's disease.

ABSTRACT:

Background

Genetic mutations in beta-glucocerebrosidase (GBA) represent the major genetic risk factor for Parkinson's disease (PD). GBA participates in both the endo-lysosomal pathway and the immune response, two important mechanisms involved in the pathogenesis of PD. However, modifiers of GBA penetrance have not yet been fully elucidated.

Methods

We characterized the transcriptomic profiles of circulating monocytes in a population of patients with PD and healthy controls (CTRL) with and without GBA variants (n = 23 PD/GBA, 13 CTRL/GBA, 56 PD, 66 CTRL) and whole blood (n = 616 PD, 362 CTRL, 127 PD/GBA, 165 CTRL/GBA). Differential expression analysis, pathway enrichment analysis, and outlier detection were performed. Ultrastructural characterization of isolated CD14+ monocytes in the four groups was also performed through electron microscopy.

Results

We observed hundreds of differentially expressed genes and dysregulated pathways when comparing manifesting and non-manifesting GBA mutation carriers. Specifically, when compared to idiopathic PD, PD/GBA showed dysregulation in genes involved in alpha-synuclein degradation, aging and amyloid processing. Gene-based outlier analysis confirmed the involvement of lysosomal, membrane trafficking, and mitochondrial processing in manifesting compared to non-manifesting GBA-carriers, as also observed at the ultrastructural levels. Transcriptomic results were only partially replicated in an independent cohort of whole blood samples, suggesting cell-type specific changes.

Conclusions

Overall, our transcriptomic analysis of primary monocytes identified gene targets and biological processes that can help in understanding the pathogenic mechanisms associated with GBA mutations in the context of PD.

SUBMITTER: Riboldi GM

PROVIDER: S-EPMC9386994 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Transcriptome deregulation of peripheral monocytes and whole blood in GBA-related Parkinson's disease.

Riboldi Giulietta Maria GM Vialle Ricardo A RA Navarro Elisa E Udine Evan E de Paiva Lopes Katia K Humphrey Jack J Allan Amanda A Parks Madison M Henderson Brooklyn B Astudillo Kelly K Argyrou Charalambos C Zhuang Maojuan M Sikder Tamjeed T Oriol Narcis J J Kumar Shilpa Dilip SD Janssen William W Sowa Allison A Comi Giacomo P GP Di Fonzo Alessio A Crary John F JF Frucht Steven J SJ Raj Towfique T

Molecular neurodegeneration 20220817 1

<h4>Background</h4>Genetic mutations in beta-glucocerebrosidase (GBA) represent the major genetic risk factor for Parkinson's disease (PD). GBA participates in both the endo-lysosomal pathway and the immune response, two important mechanisms involved in the pathogenesis of PD. However, modifiers of GBA penetrance have not yet been fully elucidated.<h4>Methods</h4>We characterized the transcriptomic profiles of circulating monocytes in a population of patients with PD and healthy controls (CTRL) ...[more]

PMID: 35978378

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Project description:BackgroundPatients with Parkinson's disease (PD) and GBA gene mutations (GBA-PD) develop nonmotor complications more frequently than noncarriers. However, an objective characterization of both cardiovascular and sudomotor autonomic dysfunction using extensive clinical and instrumental measures has never been provided so far. Survival is reduced in GBA-PD regardless of age and dementia, suggesting that other hitherto unrecognized factors are involved.ObjectivesTo provide instrumental measures of pattern and severity of autonomic dysfunction in GBA-PD and explore their correlation with other non-motor symptoms and implications for clinical practice.MethodsIn this cross-sectional study, 21 GBA-PD and 24 matched PD noncarriers underwent extensive assessment of motor and non-motor features, including neuropsychological testing. Cardiovascular autonomic function was explored through a comprehensive battery of indexes, including power spectral analysis of the R-R intervals and blood pressure short-term variability during resting state and active maneuvers. Dynamic Sweat Test was used to assess post-ganglionic sudomotor dysfunction.ResultsDespite minimal or absent clinical correlates, cardiovagal and sympathetic indexes, heart rate variability parameters and sudomotor postganglionic function were more severely impaired in GBA-PD than noncarriers (overcoming relatively preserved compensatory peripheral sympathetic function), suggesting more prominent cardiac sympatho-vagal demodulation, efferent baroreflex failure and peripheral sympathetic dysfunction in GBA-PD. Cardiovascular dysautonomia showed marginal correlations with cognitive impairment.ConclusionsCompared to PD noncarriers, GBA-PD display more severe instrumental autonomic abnormalities, which may be underestimated by purely clinical measures, despite their relevance on morbidity and mortality. This supports the necessity of implementing instrumental autonomic assessment in all GBA-PD, regardless of clinically overt symptoms.

Dataset Information

Transcriptome deregulation of peripheral monocytes and whole blood in GBA-related Parkinson's disease.

Background

Methods

Results

Conclusions

Publications

Transcriptome deregulation of peripheral monocytes and whole blood in GBA-related Parkinson's disease.

Similar Datasets

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