References of "NPJ Parkinson's Disease"
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See detailSystems level analysis of sex-dependent gene expression changes in Parkinson’s disease
Tranchevent, Leon-Charles UL; Halder, Rashi UL; Glaab, Enrico UL

in NPJ Parkinson's Disease (in press)

Parkinson’s disease (PD) is a heterogeneous disorder, and among the factors which influence the symptom profile, biological sex has been reported to play a significant role. While males have a higher age ... [more ▼]

Parkinson’s disease (PD) is a heterogeneous disorder, and among the factors which influence the symptom profile, biological sex has been reported to play a significant role. While males have a higher age-adjusted disease incidence and are more frequently affected by muscle rigidity, females present more often with disabling tremors. The molecular mechanisms involved in these differences are still largely unknown, and an improved understanding of the relevant factors may open new avenues for pharmacological disease modification. To help address this challenge, we conducted a meta-analysis of disease-associated molecular sex differences in brain transcriptomics data from case/control studies. Both sex-specific (alteration in only one sex) and sex-dimorphic changes (changes in both sexes, but with opposite direction) were identified. Using further systems level pathway and network analyses, coordinated sex-related alterations were studied. These analyses revealed significant disease-associated sex differences in mitochondrial pathways and highlight specific regulatory factors whose activity changes can explain downstream network alterations, propagated through gene regulatory cascades. Single-cell expression data analyses confirmed the main pathway-level changes observed in bulk transcriptomics data. Overall, our analyses revealed significant sex disparities in PD-associated transcriptomic changes, resulting in coordinated modulations of molecular processes. Among the regulatory factors involved, NR4A2 has already been reported to harbour rare mutations in familial PD and its pharmacological activation confers neuroprotective effects in toxin-induced models of Parkinsonism. Our observations suggest that NR4A2 may warrant further research as a potential adjuvant therapeutic target to address a subset of pathological molecular features of PD that display sex-associated profiles. [less ▲]

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See detailAge at onset as stratifier in idiopathic Parkinson's disease - effect of ageing and polygenic risk score on clinical phenotypes
Pavelka, Lukas; Rauschenberger, Armin UL; Landoulsi, Zied UL et al

in NPJ Parkinson's Disease (2022), 9(8), 102

Several phenotypic differences observed in Parkinson's disease (PD) patients have been linked to age at onset (AAO). We endeavoured to find out whether these differences are due to the ageing process ... [more ▼]

Several phenotypic differences observed in Parkinson's disease (PD) patients have been linked to age at onset (AAO). We endeavoured to find out whether these differences are due to the ageing process itself by using a combined dataset of idiopathic PD (n = 430) and healthy controls (HC; n = 556) excluding carriers of known PD-linked genetic mutations in both groups. We found several significant effects of AAO on motor and non-motor symptoms in PD, but when comparing the effects of age on these symptoms with HC (using age at assessment, AAA), only positive associations of AAA with burden of motor symptoms and cognitive impairment were significantly different between PD vs HC. Furthermore, we explored a potential effect of polygenic risk score (PRS) on clinical phenotype and identified a significant inverse correlation of AAO and PRS in PD. No significant association between PRS and severity of clinical symptoms was found. We conclude that the observed non-motor phenotypic differences in PD based on AAO are largely driven by the ageing process itself and not by a specific profile of neurodegeneration linked to AAO in the idiopathic PD patients. [less ▲]

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See detailPeripheral decarboxylase inhibitors paradoxically induce aromatic L-amino acid decarboxylase
Krüger, Rejko UL; Pavelka, Lukas UL; Mollenhauer, Brit et al

in NPJ Parkinson's Disease (2021)

Peripheral decarboxylase inhibitors (PDIs) prevent the conversion of levodopa to dopamine in the blood by the enzyme aromatic L-amino acid decarboxylase (AADC). Alterations in enzyme activity may ... [more ▼]

Peripheral decarboxylase inhibitors (PDIs) prevent the conversion of levodopa to dopamine in the blood by the enzyme aromatic L-amino acid decarboxylase (AADC). Alterations in enzyme activity may contribute to the required higher dosages of levodopa observed in many patients with Parkinson’s disease. We evaluated the effect of levodopa/PDI use on serum AADC enzyme activity. Serum AADC enzyme activity was evaluated in three independent cohorts of patients with Parkinson’s disease or parkinsonism (n = 301) and compared between patients on levodopa/PDI vs. patients not on this medication. AADC enzyme activity was elevated in 62% of patients on levodopa/PDI treatment, compared to 19% of patients not on levodopa/PDI (median 90 mU/L vs. 50 mU/L, p < 0.001). Patients with elevated AADC activity had longer disease duration and higher doses of levodopa/PDI. These findings may implicate that peripheral AADC induction could underlie a waning effect of levodopa, necessitating dose increases to maintain a sustained therapeutic effect. [less ▲]

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See detailReduced astrocytic reactivity in human brains and midbrain organoids with PRKN mutations
Kano, Masayoshi; Takanashi, Masashi; Oyama, Genko et al

in NPJ Parkinson's Disease (2020)

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See detailModeling Parkinson’s disease in midbrain-like organoids
Smits, Lisa UL; Reinhardt, Lydia; Reinhardt, Peter et al

in NPJ Parkinson's Disease (2019)

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See detailEmbryonic development of selectively vulnerable neurons in Parkinson’s disease
Oliveira, Miguel UL; Balling, Rudi UL; Smidt, Marten et al

in NPJ Parkinson's Disease (2017), 3

A specific set of brainstem nuclei are susceptible to degeneration in Parkinson’s disease. We hypothesise that neuronal vulnerability reflects shared phenotypic characteristics that confer selective ... [more ▼]

A specific set of brainstem nuclei are susceptible to degeneration in Parkinson’s disease. We hypothesise that neuronal vulnerability reflects shared phenotypic characteristics that confer selective vulnerability to degeneration. Neuronal phenotypic specification is mainly the cumulative result of a transcriptional regulatory program that is active during the development. By manual curation of the developmental biology literature, we comprehensively reconstructed an anatomically resolved cellular developmental lineage for the adult neurons in five brainstem regions that are selectively vulnerable to degeneration in prodromal or early Parkinson’s disease. We synthesised the literature on transcription factors that are required to be active, or required to be inactive, in the development of each of these five brainstem regions, and at least two differentially vulnerable nuclei within each region. Certain transcription factors, e.g., Ascl1 and Lmx1b, seem to be required for specification of many brainstem regions that are susceptible to degeneration in early Parkinson’s disease. Some transcription factors can even distinguish between differentially vulnerable nuclei within the same brain region, e.g., Pitx3 is required for specification of the substantia nigra pars compacta, but not the ventral tegmental area. We do not suggest that Parkinson’s disease is a developmental disorder. In contrast, we consider identification of shared developmental trajectories as part of a broader effort to identify the molecular mechanisms that underlie the phenotypic features that are shared by selectively vulnerable neurons. Systematic in vivo assessment of fate determining transcription factors should be completed for all neuronal populations vulnerable to degeneration in early Parkinson’s disease. [less ▲]

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