Loss-of-function caused by mutations in the parkin gene (PARK2) lead to early-onset familial Parkinson's disease. Recently, mechanistic studies proved the ability of parkin in regulating mitochondria ...homeostasis and microtubule (MT) stability. Looking at these systems during aging of PARK2 knockout mice, we found that loss of parkin induced an accelerated (over)acetylation of MT system both in dopaminergic neuron cell bodies and fibers, localized in the substantia nigra and corpus striatum, respectively. Interestingly, in PARK2 knockout mice, changes of MT stability preceded the alteration of mitochondria transport. Moreover, in-cell experiments confirmed that loss of parkin affects mitochondria mobility and showed that this defect depends on MT system as it is rescued by paclitaxel, a well-known MT-targeted agent. Furthermore, both in PC12 neuronal cells and in patients' induced pluripotent stem cell–derived midbrain neurons, we observed that parkin deficiencies cause the fragmentation of stable MTs. Therefore, we suggest that parkin acts as a regulator of MT system during neuronal aging, and we endorse the hypothesis that MT dysfunction may be crucial in the pathogenesis of Parkinson's disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The role of microtubule (MT) dysfunction in Parkinson's disease is emerging. It is still unknown whether it is a cause or a consequence of neurodegeneration. Our objective was to assess whether ...alterations of MT stability precede or follow axonal transport impairment and neurite degeneration in experimental parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57Bl mice. MPTP induced a time- and dose-dependent increase in fibres with altered mitochondria distribution, and early changes in cytoskeletal proteins and MT stability. Indeed, we observed significant increases in neuron-specific βIII tubulin and enrichment of deTyr tubulin in dopaminergic neurons. Finally, we showed that repeated daily administrations of the MT stabilizer Epothilone D rescued MT defects and attenuated nigrostriatal degeneration induced by MPTP. These data suggest that alteration of ΜΤs is an early event specifically associated with dopaminergic neuron degeneration. Pharmacological stabilization of MTs may be a viable strategy for the management of parkinsonism.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Emerging evidence supports that altered α-tubulin acetylation occurs in Parkinson's disease (PD), a neurodegenerative disorder characterized by the deposition of α-synuclein fibrillary aggregates ...within Lewy bodies and nigrostriatal neuron degeneration. Nevertheless, studies addressing the interplay between α-tubulin acetylation and α-synuclein are lacking. Here, we investigated the relationship between α-synuclein and microtubules in primary midbrain murine neurons and the substantia nigra of post-mortem human brains. Taking advantage of immunofluorescence and Proximity Ligation Assay (PLA), a method allowing us to visualize protein-protein interactions in situ, combined with confocal and super-resolution microscopy, we found that α-synuclein and acetylated α-tubulin colocalized and were in close proximity. Next, we employed an α-synuclein overexpressing cellular model and tested the role of α-tubulin acetylation in α-synuclein oligomer formation. We used the α-tubulin deacetylase HDAC6 inhibitor Tubacin to modulate α-tubulin acetylation, and we evaluated the presence of α-synuclein oligomers by PLA. We found that the increase in acetylated α-tubulin significantly induced α-synuclein oligomerization. In conclusion, we unraveled the link between acetylated α-tubulin and α-synuclein and demonstrated that α-tubulin acetylation could trigger the early step of α-synuclein aggregation. These data suggest that the proper regulation of α-tubulin acetylation might be considered a therapeutic strategy to take on PD.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Summary Background & aims Parkinson's disease (PD) patients can benefit considerably from appropriate nutritional care, particularly from diet. However, there is limited evidence on the eating habits ...of PD patients and their relationship with the features of the disease. Methods We conducted a large case–control study. Consecutive PD patients ( N = 600) receiving systematic nutritional care and healthy controls ( N = 600) matched (1:1) for age, gender, education, physical activity level and residence were studied using a 66-item food frequency questionnaire. The relationship between dietary habits and the following features of PD were investigated in patients: body weight, energy balance, constipation, and levodopa therapy (dose) and its related motor complications. Results PD patients had lower BMI and reported higher food intake than controls. BMI was found to be inversely associated with disease duration and severity, and levodopa-related motor complications, whereas energy intake was positively associated with these variables. An increase in protein intake by 10 g over physiological requirements (0.8 g/kg/day) corresponded to a mean increase in levodopa dose of 0.7 mg/kg/day. Constipation was also associated with higher levodopa requirements. Finally, protein intake and its distribution throughout the day influenced levodopa-related motor complications. Conclusion The management of protein intake and the treatment of constipation should be considered to be an integral part of the care of PD patients. Attention should always be focused on energy intake also. This would result in the maintenance of nutritional status, the optimization of levodopa-therapy and the minimization of its related motor complications.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Cortical dysfunctioning significantly contributes to the pathogenesis of motor symptoms in Parkinson's disease (PD).
We aimed at testing whether an acute levodopa administration has measurable and ...specific cortical effects possibly related to striatal dopaminergic deficit.
In thirteen PD patients, we measured the electroencephalographic responses to transcranial magnetic stimulation (TMS/EEG) of the supplementary motor area and superior parietal lobule (n = 8) before and after an acute intake of levodopa. We also performed a single-photon emission computed tomography and 123IN-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane to identify the more affected and the less affected brain side in each patient, according to the dopaminergic innervation loss of the putamen. Cortical excitability changes before and after an acute intake of levodopa were computed and compared between the more and the less affected brain side at the single-patient as well as at the group level.
We found that levodopa intake induces a significant increase (P < 0.01) of cortical excitability nearby the supplementary motor area in the more affected brain side, greater (P < 0.025) than in the less affected brain side. Notably, cortical excitability changes nearby the superior parietal lobule were not statistically significant.
These results strengthen the idea that dysfunction of specific cortico-subcortical circuits may contribute to pathophysiology of PD symptoms. Most important, they support the use of navigated TMS/EEG as a non-invasive tool to better understand the pathophysiology of PD.
•Cortical excitability was assessed before and after levodopa intake using TMS/EEG.•Levodopa intake induced an increase of excitability nearby the supplementary motor area.•This increase was higher on the brain side ipsilateral to the more affected putamen.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
α-synuclein is a small protein that is mainly expressed in the synaptic terminals of nervous tissue. Although its implication in neurodegeneration is well established, the physiological role of ...α-synuclein remains elusive. Given its involvement in the modulation of synaptic transmission and the emerging role of microtubules at the synapse, the current study aimed at investigating whether α-synuclein becomes involved with this cytoskeletal component at the presynapse. We first analyzed the expression of α-synuclein and its colocalization with α-tubulin in murine brain. Differences were found between cortical and striatal/midbrain areas, with substantia nigra pars compacta and corpus striatum showing the lowest levels of colocalization. Using a proximity ligation assay, we revealed the direct interaction of α-synuclein with α-tubulin in murine and in human brain. Finally, the previously unexplored interaction of the two proteins in vivo at the synapse was disclosed in murine striatal presynaptic boutons through multiple approaches, from confocal spinning disk to electron microscopy. Collectively, our data strongly suggest that the association with tubulin/microtubules might actually be an important physiological function for α-synuclein in the synapse, thus suggesting its potential role in a neuropathological context.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Both motor and non-motor symptoms could contribute to significant deterioration of psychological well-being in patients with Parkinson's disease (PD). However, its assessment has been only indirectly ...evaluated using tools based on health-related quality of life (HRQoL), such as the PDQ-39 scale.
To evaluate psychological well-being in PD using a specific tool of assessment, the Psychological Well-being Scale (PWS), and its clinical correlates.
This article reports data of patients' perception of health state, as measured by means of the PWS, from an epidemiological, cross-sectional study conducted in Italian PD patients (FORTE Study). We tested possible relationship between well-being and clinical characteristics including fatigue, depression, sleep disruption and HRQoL.
272 patients completed the PWS questionnaire. Significant and clinically-relevant correlations were found between PWS total score and Parkinson's Fatigue Scale, Beck Depression Inventory, UPDRS Section I, PD Sleep Scale and PDQ-39 for HRQoL scores. Only clinically negligible correlations were found between PWS and motor scores.
Non-motor symptoms have a significant impact on psychological well-being in PD patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Current protocols for in vitro differentiation of human induced pluripotent stem cells (hiPSCs) to generate dopamine (DA) neurons are laborious and time‐expensive. In order to accelerate the overall ...process, we have established a fast protocol by expressing the developmental transcription factors ASCL1, NURR1, and LMX1A. With this method, we were able to generate mature and functional dopaminergic neurons in as few as 21 days, skipping all the intermediate steps for inducting and selecting embryoid bodies and rosette‐neural precursors. Strikingly, the resulting neuronal conversion process was very proficient, with an overall efficiency that was more than 93% of all the coinfected cells. hiPSC‐derived DA neurons expressed all the critical molecular markers of the DA molecular machinery and exhibited sophisticated functional features including spontaneous electrical activity and dopamine release. This one‐step protocol holds important implications for in vitro disease modeling and is particularly amenable for exploitation in high‐throughput screening protocols.
This study describes a straightforward one‐step protocol for differentiating human induced pluripotent stem cells (hiPSCs) into dopamine neurons based on the overexpression of the three cell lineage‐specific transcription factors ASCL1, NURR1, and LMX1A. This protocol was applied to hiPSCs derived from fetal and Parkinson's disease patient adult fibroblasts, and both cases resulted in a high number of TH+ neurons, which showed dopaminergic and midbrain markers after 2 weeks and robust functional properties from 21 days.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract Background Swallowing disturbances are an important issue in Parkinson's disease (PD) as several studies have shown that they are associated with increased risk of aspiration pneumonia and ...mortality. Information about factors related to swallowing disturbances, such as disease duration, age at assessment and concomitant dementia, is limited and would be useful for their management. Methods All consecutive PD out-patients evaluated at a movement disorders clinic over a 7-year period (2007–2014), were included in the present retrospective study. Presence of symptomatic swallowing disturbances was assessed using the specific item of the Non Motor Symptom Questionnaire. Results In the whole PD population ( N = 6462), prevalence of symptomatic swallowing disturbances was 11.7% (95%CI, 10.9–12.5). Multivariable logistic regression analysis (adjusted for education) disclosed a significant interaction between disease duration and gender ( P = 0.009). In both gender strata, swallowing disturbances were significantly associated with longer disease duration and dementia ( P < 0.001 for all). A significant effect for age at assessment was also found in male patients. In non-demented patients, swallowing disturbances were associated with male gender, age and disease duration ( P < 0.02 for all). In demented patients an association was found only with male gender ( P = 0.018) and disease duration ( P < 0.001). Conclusions Gender, age, disease duration and dementia all seem to contribute to the occurrence of swallowing disturbances independently. However, the role played by these factors in sub-groups of patients stratified by gender and concomitant dementia suggests that swallowing disturbances are likely related to different neuro-degenerative patterns within the brain. The underlying mechanisms deserve further investigation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Pathological gambling (PG) represents a behavioral side effect of dopamine replacement therapy in a minority of patients with Parkinson's disease (PD). Using striatal dopamine transporter ...(DAT) with single photon emission tomography we assessed presynaptic dopaminergic function in 8 PD patients with PG, 21 matched PD control subjects, and 14 healthy subjects. Statistical Parametric Mapping was applied for image analysis. The analysis of variance (ANOVA) revealed that the three groups differed in dorsal and ventral striata bilaterally. The post-hoc analysis displayed a reduced tracer binding in the ventral striatum of PD patients with PG compared to PD controls, possibly reflecting either a reduction of mesolimbic projections or, alternatively, a lower membrane DAT expression on presynaptic terminals. The latter hypothesis is most likely given that the functional reduction of presynaptic reuptake would be more consistent with the increased dopamine levels in the ventral striatum recently reported in PD gamblers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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