The common presence of alpha-synuclein aggregates in peripheral autonomic neurons may represent an early presymptomatic phase in the development of Lewy body disorders.

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The authors report the results of a multicentric study designed to assess the tolerability and clinical effects of bilateral pallidal DBS on motor impairment, functional disability, quality of life, pain and mood in patients with medically refractory primary generalised or segmental dystonia.

Mutations in the parkin gene cause autosomal-recessive, juvenile-onset parkinsonism, and parkin dysfunction may also play a role in the pathogenesis of sporadic Parkinson disease (PD). Although its precise function remains largely unknown, parkin seems to play a neuroprotective role. Several studies indicate that changes in parkin solubility induced by post-translational modifications, such as S-nitrosylation or dopamine modification, comprise one mechanism of parkin inactivation associated with disease. Protein phosphorylation events have recently been linked to the molecular mechanism(s) underlying PD, but the role of this post-translational modification for parkin function has remained unclear. Here we report that compound phosphorylation of parkin by both casein kinase I and cyclin-dependent kinase 5 (cdk5) decreases parkin solubility, leading to its aggregation and inactivation. Combined kinase inhibition partially reverses the aggregative properties of several pathogenic point mutants in cultured cells. Enhanced parkin phosphorylation is detected in distinct brain areas of individuals with sporadic PD and correlates with increases in the levels of p25, the activator of cdk5. These findings indicate that casein kinase I and cdk5 may represent novel combinatorial therapeutic targets for treating PD.

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Background: Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is favoured over bilateral globus pallidus internus (Gpi) DBS for symptomatic treatment of advanced Parkinson's disease (PD) due to the possibility of reducing medication, despite lack of definitive comparative evidence. Objective: To analyse outcomes after one year of bilateral Gpi or STN DBS, with consideration of influence of selection bias on the pattern of postsurgical medication change. Methods: The first patients to undergo bilateral Gpi (n = 10) or STN (n = 10) DBS at our centre were studied. They were assessed presurgically and one year after surgery (CAPIT protocol). Results: Before surgery the Gpi DBS group had more dyskinesias and received lower doses of medication. At one year, mean reduction in UPDRS off medication score was 35% and 39% in the Gpi and STN groups, respectively (non-significant difference). Dyskinesias reduced in proportion to presurgical severity. The levodopa equivalent dose was significantly reduced only in the STN group (24%). This study highlights the absence of significant differences between the groups in clinical scales and medication dose at one year. In the multivariate analysis of predictive factors for off-state motor improvement, the presurgical levodopa equivalent dose showed a direct relation in the STN and an inverse relation in the Gpi group. Conclusion: Differences in the patterns of medication change after Gpi and STN DBS may be partly due to a patient selection bias. Both procedures may be equally useful for different subgroups of patients with advanced PD, Gpi DBS especially for patients with lower threshold for dyskinesia.

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Background The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. Objectives To perform the largest PD genome‐wide association study restricted to a single country. Methods We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population‐specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease‐associated loci, heritability estimates, genetic correlations, and burden analyses. Results We identified a novel population‐specific genome‐wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome‐wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA‐DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non‐Spanish origin. Seventeen PD‐related genes showed functional consequence by two‐sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. Conclusions Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine‐mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society