Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Keo, Arlin; Mahfouz, Ahmed; Ingrassia, Angela; Meneboo, Jean Pascal; Villenet, Céline; Mutez, Eugénie; Comptdaer, Thomas; Lelieveldt, Boudewijn P. F.; Figeac, Martin; Chartier-Harlin, Marie-Christine; Berg, Wilma D. J. van de; Hilten, Jacobus J. van; Reinders, Marcel J. T.

doi:10.1038/s42003-020-0804-9

Cited by 65 publications

(43 citation statements)

References 50 publications

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“…Several ‘causative’ genes, none completely penetrant, and a vast array of susceptibility genes governing widely-varying metabolic processes have been elucidated [ 26 ]. RNA expression studies demonstrate the complex genetic and biologic heterogeneity of PD [ 27 ]. It is a testament to this complexity that metabolomics are now being used to measure the downstream effects of a vast array of contributory genetic, environmental and physiological processes [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Parkinson’s Disease Subtypes: Critical Appraisal and Recommendations

Mestre

Fereshtehnejad

Berg

et al. 2021

JPD

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Background: In Parkinson's disease (PD), there is heterogeneity in the clinical presentation and underlying biology. Research on PD subtypes aims to understand this heterogeneity with potential contribution for the knowledge of disease pathophysiology, natural history and therapeutic development. There have been many studies of PD subtypes but their impact remains unclear with limited application in research or clinical practice. Objective: To critically evaluate PD subtyping systems. Methods: We conducted a systematic review of PD subtypes, assessing the characteristics of the studies reporting a subtyping system for the first time. We completed a critical appraisal of their methodologic quality and clinical applicability using standardized checklists. Results: We included 38 studies. The majority were cross-sectional (n = 26, 68.4%), used a data-driven approach, and nonclinical biomarkers were rarely used (n = 5, 13.1%). Motor characteristics were the domain most commonly reported to differentiate PD subtypes. Most of the studies did not achieve the top rating across items of a Methodologic Quality checklist. In a Clinical Applicability Checklist, the clinical importance of differences between subtypes, potential treatment implications and applicability to the general population were rated poorly, and subtype stability over time and prognostic value were largely unknown. Conclusion: Subtyping studies undertaken to date have significant methodologic shortcomings and most have questionable clinical applicability and unknown biological relevance. The clinical and biological signature of PD may be unique to the individual, rendering PD resistant to meaningful cluster solutions. New approaches that acknowledge the individual-level heterogeneity and that are more aligned with personalized medicine are needed.

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Section: Discussionmentioning

confidence: 99%

Parkinson’s Disease Subtypes: Critical Appraisal and Recommendations

Mestre

Fereshtehnejad

Berg

et al. 2021

JPD

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“…This discrepancy may be associated with disease models because Yu et al [ 33 ] did not observe any significant changes in ROS formation between non-Tg and endophilin A1 Tg slices under normal conditions. Further, in patients with Parkinson’s disease, endophilin A1 has been reported as one of the candidate risk genes [ 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Tat-Endophilin A1 Fusion Protein Protects Neurons from Ischemic Damage in the Gerbil Hippocampus: A Possible Mechanism of Lipid Peroxidation and Neuroinflammation Mitigation as Well as Synaptic Plasticity

Jung

Kwon

Kim

et al. 2021

Cells

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The present study explored the effects of endophilin A1 (SH3GL2) against oxidative damage brought about by H2O2 in HT22 cells and ischemic damage induced upon transient forebrain ischemia in gerbils. Tat-SH3GL2 and its control protein (Control-SH3GL2) were synthesized to deliver it to the cells by penetrating the cell membrane and blood–brain barrier. Tat-SH3GL2, but not Control-SH3GL2, could be delivered into HT22 cells in a concentration- and time-dependent manner and the hippocampus 8 h after treatment in gerbils. Tat-SH3GL2 was stably present in HT22 cells and degraded with time, by 36 h post treatment. Pre-incubation with Tat-SH3GL2, but not Control-SH3GL2, significantly ameliorated H2O2-induced cell death, DNA fragmentation, and reactive oxygen species formation. SH3GL2 immunoreactivity was decreased in the gerbil hippocampal CA1 region with time after ischemia, but it was maintained in the other regions after ischemia. Tat-SH3GL2 treatment in gerbils appreciably improved ischemia-induced hyperactivity 1 day after ischemia and the percentage of NeuN-immunoreactive surviving cells increased 4 days after ischemia. In addition, Tat-SH3GL2 treatment in gerbils alleviated the increase in lipid peroxidation as assessed by the levels of malondialdehyde and 8-iso-prostaglandin F2α and in pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, and interleukin-6; while the reduction of protein levels in markers for synaptic plasticity, such as postsynaptic density 95, synaptophysin, and synaptosome associated protein 25 after transient forebrain ischemia was also observed. These results suggest that Tat-SH3GL2 protects neurons from oxidative and ischemic damage by reducing lipid peroxidation and inflammation and improving synaptic plasticity after ischemia.

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“…Moreover, we have to take into consideration that we identified genes that already show low baseline expression levels in the brain. It also has to be noted that the use of healthy brains from the AHBA, although sub-optimal, does not limit us per se in the phenotype of interest, as it already has been shown to be useful in identifying genes related to diseases and disorders ( Keo et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of the stress network in individuals at risk for schizophrenia

Meijer

Keo

Leeuwen

et al. 2021

Neurobiology of Stress

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The biological mechanisms underlying inter-individual differences in human stress reactivity remain poorly understood. We aimed to identify the molecular underpinning of aberrant neural stress sensitivity in individuals at risk for schizophrenia. Linking mRNA expression data from the Allen Human Brain Atlas to task-based fMRI revealed 201 differentially expressed genes in cortex-specific brain regions differentially activated by stress in individuals with low (healthy siblings of schizophrenia patients) or high (healthy controls) stress sensitivity. These genes are associated with stress-related psychiatric disorders (e.g. schizophrenia and anxiety) and include markers for specific neuronal populations (e.g. ADCYAP1 , GABRB1 , SSTR1 , and TNFRSF12A ), neurotransmitter receptors (e.g. GRIN3A , SSTR1 , GABRB1 , and HTR1E ), and signaling factors that interact with the corticosteroid receptor and hypothalamic-pituitary-adrenal axis (e.g. ADCYAP1 , IGSF11, and PKIA ). Overall, the identified genes potentially underlie altered stress reactivity in individuals at risk for schizophrenia and other psychiatric disorders and play a role in mounting an adaptive stress response in at-risk individuals, making them potentially druggable targets for stress-related diseases.

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Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Cited by 65 publications

References 50 publications

Parkinson’s Disease Subtypes: Critical Appraisal and Recommendations

Parkinson’s Disease Subtypes: Critical Appraisal and Recommendations

Tat-Endophilin A1 Fusion Protein Protects Neurons from Ischemic Damage in the Gerbil Hippocampus: A Possible Mechanism of Lipid Peroxidation and Neuroinflammation Mitigation as Well as Synaptic Plasticity

Molecular characterization of the stress network in individuals at risk for schizophrenia

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