Background-Recent studies indicate an increased frequency of mutations in the gene for Gaucher disease, glucocerebrosidase (GBA), among patients with Parkinson disease. An international collaborative study was conducted to ascertain the frequency of GBA mutations in ethnically diverse patients with Parkinson disease.

Mitochondria likely play a role in Parkinson's disease (PD) neurodegeneration. We modelled PD by creating cytoplasmic hybrid (cybrid) cell lines in which endogenous mitochondrial DNA (mtDNA) from PD or control subject platelets was expressed within human teratocarcinoma (NT2) cells previously depleted of endogenous mtDNA. Complex I activity was reduced in both PD cybrid lines and in the platelet mitochondria used to generate them. Under basal conditions PD cybrids had less ATP, more LDH release, depolarized mitochondria, less mitochondrial cytochrome c, and higher caspase 3 activity. Equivalent MPP + exposures are more likely to trigger programmed cell death in PD cybrid cells than in control cybrid cells. Our data support a relatively upstream role for mitochondrial dysfunction in idiopathic PD.

Sensory deficits have been documented in Parkinson's disease, in particular within the visual domain. However, ageing factors related to the brain and to neural and non-neural ocular structures could explain some of the previously reported results, in particular the claimed impairment within the koniocellular pathway. This study addressed visual impairment attributable to the magno- (luminance), parvo- (red-green) and koniocellular (blue-yellow) pathways in a population of Parkinson's disease patients. To avoid potentially confounding factors, all subjects underwent a full neurophthalmological assessment which led to exclusion of subjects with increased intraocular pressure, diabetes even in the absence of retinopathy, and ocular abnormalities (from a total of 72 patients' eyes, 12 were excluded). Both parvo- and koniocellular pathways were studied by means of contrast sensitivity (CS) measurements along protan, tritan and deutan axes and also by fitting chromatic discrimination ellipses using eight measured contrast axes. Magnocellular function was assessed, using stimuli that induce a frequency doubling illusion, in 17 locations in the fovea and periphery. Achromatic (luminance modulation) thresholds were significantly higher in Parkinson's disease both in foveal and peripheral locations. A significant impairment was observed along protan and deutan axes, but only marginally along the tritan axis. These results were corroborated by a significant elongation of chromatic discrimination ellipses in our Parkinson's disease group. Correlation analysis showed that achromatic and chromatic CS measures were independent, which implies that multiple visual pathways are affected independently in Parkinson's disease. Magnocellular impairment was significantly correlated with age and disease stage, in contrast to the measured chromatic deficits. We conclude that in Parkinson's disease, independent damage occurs in the early magno- and parvocellular pathways. Furthermore, traditional koniocellular probing strategies in Parkinson's disease may be confounded by ageing factors, which may reconcile the previously reported controversial findings concerning chromatic impairment in Parkinson's disease.

Mutations in the gene encoding beta-glucocerebrosidase, a lysosomal degrading enzyme, have recently been associated with the development of Parkinson disease. Here we report the results found in a cohort of Portuguese Parkinson disease patients and healthy age-matched controls for mutations in the aforementioned gene. This screening was accomplished by sequencing the complete open-reading frame, as well as intron/exon boundaries, of the glucocerebrosidase gene, in a total of 230 patients and 430 controls. We have found an increased number of Parkinson disease patients presenting mutations in GBA when compared to controls. These results, together with recent literature, clearly suggest a role of glucocerebrosidase in the development of Parkinson disease.

LRRK2 mutations have recently been described in families with Parkinson's disease. Here we show that one of them (G2019S) is present in 6% (7 of 124) unrelated cases of disease in a clinic-based sample series from central Portugal, but not present in 126 controls from the same population. Thus, LRRK2 mutations appear to be a common cause of typical Parkinson's disease and as such will alter clinical practice.

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Machado Joseph Disease (MJD) is the most frequent autosomal dominantly inherited cerebellar ataxia caused by the over-repetition of a CAG trinucleotide in the ATXN3 gene. This expansion translates into a polyglutamine tract within the ataxin-3 protein that confers a toxic gain-of-function to the mutant protein ataxin-3, contributing to protein misfolding and intracellular accumulation of aggregates and neuronal degeneration. Autophagy impairment has been shown to be one of the mechanisms that contribute for the MJD phenotype. Here we investigated whether this phenotype was present in patient-derived fibroblasts, a common somatic cell type used in the derivation of induced pluripotent stem cells and subsequent differentiation into neurons, for in vitro disease modeling. We generated and studied adult dermal fibroblasts from 5 MJD patients and 4 healthy individuals and we found that early passage MJD fibroblasts exhibited autophagy impairment with an underlying mechanism of decreased autophagosome production. The overexpression of beclin-1 on MJD fibroblasts reverted partially autophagy impairment by increasing the autophagic flux but failed to increase the levels of autophagosome production. Overall, our results provide a well-characterized MJD fibroblast resource for neurodegenerative disease research and contribute for the understanding of mutant ataxin-3 biology and its molecular consequences.

Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.