•Protein degradation in cultured peripheral blood mononuclear cells is reduced in PD patients.•Macroautophagy is impaired in PBMCs of PD patients.•Chaperone-Mediated Autophagy is impaired in PBMCs of ...PD patients.
Alpha-synuclein aggregation is considered one of the main causes of Parkinson’s Disease (PD). Malfunction of autophagy-lysosomal pathways is believed to be an underlying mechanism of α-synuclein aggregation. Although such malfunction has been observed in PD brains, it is unclear whether it may also occur in extraneuronal tissues.
To assess lysosome-mediated protein degradation in cultured Peripheral Blood Mononuclear Cells (PBMCs) of PD patients and healthy controls.
Total protein degradation in cultured PBMCs was measured by labelling the cells with 3H-leucine using pulse-chase experiments. Different inhibitors were used to measure a range of autophagic pathways.
Protein degradation through the main autophagic pathways is reduced in PD patients (n = 18) compared to age- and sex-matched healthy controls (n = 18), (macroautophagy, p = .018; Chaperone-Mediated autophagy, p = .04; and total lysosomal function, p = .007).
Lysosomal dysfunction is present in cultured PBMCs of PD patients, suggesting that it may reflect a systemic feature of the disease.
•Erythrocyte membrane α-syn dimer is elevated in PD patients with no known mutations.•Erythrocyte membrane α-syn dimer is elevated in PD patients with GBA mutations.•There is no α-syn dimer level ...difference in p.A53T α-syn mutation carriers.•The increased α-synuclein dimer levels may be due to altered lipid composition of the erythrocyte membrane.
Variations of α-synuclein levels or species have been reported in Parkinson’s Disease (PD). There has been little systematic examination of erythrocytes, a rich source of α-synuclein.
Erythrocyte membranes were obtained from PD patients (mutation carriers in the α-synuclein gene (A53T-PD) and glucocerebrosidase gene (GBA-PD) (n=18 each), and patients without known mutations (GU-PD, n=56)), and age-/sex-matched controls (n=56). Levels of monomeric and dimeric α-synuclein were assessed using Western immunoblotting.
A statistically significant increase of α-synuclein dimer and dimer to monomer ratio was found in GBA-PD and GU-PD. In contrast, dimer levels of A53T-PD were not different from controls. No difference was found in α-synuclein monomer levels.
The increased α-synuclein dimer in GBA-PD and GU-PD is suggestive of an apparent systemic dysfunction causing the dimerization, and potentially oligomerization, of α-synuclein. These results may have implications for PD pathogenesis and biomarker development.
1) to evaluate the efficacy of medical cannabinoids (MC) by appraising the quality of evidence from clinical studies 2) to explore the factors hampering the MC use in clinical practice of Parkinson's ...disease (PD).
We performed a systematic review through various databases. The quality of 14 studies was assessed by Cochrane risk bias (5 randomized controlled trials- RCT) and Newcastle-Ottawa scale (9 uncontrolled studies).
The positive effects on motor (5 studies) and non-motor symptoms (4 studies) described in uncontrolled studies have not been confirmed by the few and small RCTs. Only one RCT found a reduction of levodopa-induced dyskinesias, another a reduction in anxiety and tremor amplitude in an anxiogenic situation, while the remaining three without effect on motor/non-motor symptoms. Physical and psychological symptoms are among the most common side effects.
There is insufficient evidence to reform international legislation regarding cannabis use in PD practice.
•There is insufficient evidence to recommend the safe use of cannabis for motor symptoms in PD.•MC should not be encouraged, except for a trial or selected patients with refractory non-motor symptoms (such as pain).•Well- designed RCTs are needed to establish evidence, which will inform the so far inconsistent MC legislation in PD.
The aim of this study is to investigate the association between environmental factors (smoking, coffee, pesticide exposure) and Parkinson's disease (PD) subtypes (early-onset, mid-and-late onset, ...familial and sporadic) in the Greek population.
The Hellenic Biobank of PD recorded information of PD cases and controls from two centers in Greece during 2006–2017. Patients with the A53T mutation in SNCA or GBA mutations were excluded. Associations of environmental factors with PD overall (and PD subtypes) versus controls were explored with logistic regression models adjusting for age, gender and each environmental factor.
686 patients and 356 controls were included. Smoking was associated with a reduced risk of PD overall (OR 0.48, 95% CI 0.35–0.67), mid-and-late onset (0.46, 0.32–0.66), familial (0.53, 0.34–0.83) and sporadic (0.46, 0.32–0.65), but not early-onset PD. There was an inverse linear association with pack-years of smoking, except for early-onset PD. Early-onset PD was the only PD subtype inversely associated with coffee consumption when dichotomously treated. Compared to never-coffee drinkers, only those at the upper tertile had lower odds for PD overall (0.52, 0.29–0.91), early-onset (0.16, 0.05–0.53) and familial PD (0.36, 0.17–0.75). No associations were found between pesticides and PD.
Our study shows that the well-known negative association of smoking with PD occurs across all PD subtypes in the Greek population, apart from early-onset PD. Early-onset PD was also most strongly inversely associated with coffee consumption, highlighting a potential distinct underlying physiopathology in this PD subset that may involve specific gene-environment interactions.
•Smoking is inversely associated with mid-late but not early-onset PD.•Smoking is inversely associated with both familial and sporadic PD.•Smoking pack-years are inversely linearly associated with PD.•Heavy coffee intake is inversely associated with PD overall.•Heavy coffee intake is inversely associated only with early-onset and familial PD subtypes.
Previous epidemiological evidence has established the co-occurrence of malignant melanoma (MM) and Parkinson's disease (PD). Shared molecular mechanisms have been proposed to be implicated in this ...relationship. The aim of the present study was to assess the prevalence of MM in patients with sporadic and genetic types of PD, as well as in asymptomatic carriers of PD-related genes.
Data regarding past medical history and concomitant disease of 1416 patients with PD (including 20 participants with prodromal disease who phenoconverted to PD), 275 healthy controls (HCs) and 670 asymptomatic carriers of PD-related genes were obtained from the database of the Parkinson's Progression Markers Initiative (PPMI). Focus was placed on information about a medical record of MM. We also retrieved data regarding the genetic status of selected PPMI participants with a positive MM history.
In total, 46 patients with PD reported a positive MM history. Concerning the genetic forms of PD, nine of these PD patients (2.47%) carried a Leucine Rich Repeat Kinase 2 (LRRK2) gene mutation (mainly the G2019S), while eight (4.49%) harbored a Glucocerebrosidase (GBA) gene mutation (mainly the N370S). No alpha-synuclein (SNCA) gene mutation was identified in patients with an MM history. The remaining 29 PD patients (3.5%) were genetically undetermined. In total, 18 asymptomatic carriers of PD-related genes had a positive medical history for MM: among them, 10 carried an LRRK2 gene mutation (2.69%) and 10 a GBA gene mutation (3.51%) (2 were dual carriers). MM history was identified for seven HCs (2.5%).
We replicated the previously reported association between genetically undetermined PD (GU-PD) and MM. A correlation of LRRK2 mutations with the development of MM could not be verified in either symptomatic PD patients or asymptomatic carriers, implicating distinct pathogenetic mechanisms as compared to GU-PD. Importantly, despite the limited literature evidence on Gaucher disease, this study highlights for the first time the relatively high prevalence of MM among asymptomatic and symptomatic PD GBA mutation carriers, with potential clinical implications.
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