Deep brain stimulation in a Parkinson's disease patient with calcifications and a mutation in the SLC20A2 gene.

A patient with Parkinson's disease (PD) who was examined as a candidate for DBS was initially rejected due to extensive brain calcifications. Upon second opinion and planning of trajectories she underwent successful surgery. Genetic analyses identified a mutation in SLC20A2, a gene known to cause brain calcifications, but no mutation known to cause PD was found.

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Neuropathological findings in PINK1-associated Parkinson's disease.

INTRODUCTION: Biallelic mutations in PTEN-induced putative kinase 1 (PINK1) is a relatively common cause of autosomal recessive early-onset Parkinson's disease (PD). However, only three PINK1 patients with brain autopsy have been reported in the literature. METHODS: We describe the clinical and pathological characteristics of a patient with early-onset PD. We screened for copy number variants SNCA, PRKN, PINK1, DJ-1, ATP13A2, LPA and TNFRSF9 by multiplex ligation-dependent probe amplification (MLPA), and subsequently we performed whole-exome sequencing. RESULTS: Clinically the patient presented with typical parkinsonism that responded well to levodopa. After 23 years of disease she had a bilateral GPi deep brain stimulation (DBS) surgery. Genetic analyses revealed a heterozygous exon 4-5 deletion and a homozygous exon 1 [c. 230T > C (p.Leu77Pro)] mutation in PINK1. Post-mortem neuropathological examination after more than 30 years of disease revealed gliosis and a large loss of melanin-containing neurons in the substantia nigra. Lewy body pathology was evident in substantia nigra, temporal cortex, locus coeruleus and the parahippocampal region. CONCLUSION: We describe the first clinical and pathological characterization of a PINK1 patient with a typical disease presentation and long disease duration. Previous reports describe two patients with Lewy-related pathologies, albeit with differential distribution, and one patient with no Lewy-related pathology. Hence, it seems that only two patients with parkinsonism due to mutations in PINK1 are consistent with α-synucleinopathy distribution like that seen in the majority of cases with sporadic PD. Our data further extend the clinicopathological characterization of PINK1-associated PD.

Cell-free expression of a functional pore-only sodium channel.

Voltage-gated sodium channels participate in the propagation of action potentials in excitable cells. Eukaryotic Navs are pseudo homotetrameric polypeptides, comprising four repeats of six transmembrane segments (S1-S6). The first four segments form the voltage-sensing domain and S5 and S6 create the pore domain with the selectivity filter. Prokaryotic Navs resemble these characteristics, but are truly tetrameric. They can typically be efficiently synthesized in bacteria, but production in vitro with cell-free synthesis has not been demonstrated. Here we report the cell-free expression and purification of a prokaryotic tetrameric pore-only sodium channel. We produced milligram quantities of the functional channel protein as characterized by size-exclusion chromatography, infrared spectroscopy and electrophysiological recordings. Cell-free expression enables advanced site-directed labelling, post-translational modifications, and special solubilization schemes. This enables next-generation biophysical experiments to study the principle of sodium ion selectivity and transport in sodium channels.