Familial genes in sporadic disease: Common variants of a-Synuclein gene associate with Parkinson’s disease

Genetic variation of the alpha-synuclein gene (SNCA) is known to cause familial parkinsonism, however the role of SNCA variants in sporadic Parkinson's disease (PD) remains elusive. The present study identifies an association of common SNCA polymorphisms with disease susceptibility in a series of Irish PD patients. There is evidence for association with alternate regions, of protection and risk which may act independently/synergistically, within the promoter region (Rep1; OR: 0.59, 95% CI: 0.37-0.84) and the 3'UTR of the gene (rs356165; OR: 1.67, 95% CI: 1.08-2.58). Given previous reports of association a collaborative effort is required which may exploit global linkage disequilibrium patterns for SNCA and standardise polymorphic markers used in each population. It is now crucial to identify the susceptibility allele and elucidate its functionality which may generate a therapeutic target for PD.

Synthesis of Walking Sounds for Alleviating Gait Disturbances in Parkinson’s Disease

Managing gait disturbances in people with Parkinson’s disease is a pressing challenge, as symptoms can contribute to injury and morbidity through an increased risk of falls. While drug-based interventions have limited efficacy in alleviating gait impairments, certain non-pharmacological methods, such as cueing, can also induce transient improvements to gait. The approach adopted here is to use computationally-generated sounds to help guide and improve walking actions. The first method described uses recordings of force data taken from the steps of a healthy adult which in turn were used to synthesize realistic gravel-footstep sounds that represented different spatio-temporal parameters of gait, such as step duration and step length. The second method described involves a novel method of sonifying, in real time, the swing phase of gait using real-time motion-capture data to control a sound synthesis engine. Both approaches explore how simple but rich auditory representations of action based events can be used by people with Parkinson’s to guide and improve the quality of their walking, reducing the risk of falls and injury. Studies with Parkinson’s disease patients are reported which show positive results for both techniques in reducing step length variability. Potential future directions for how these sound approaches can be used to manage gait disturbances in Parkinson’s are also discussed.

Balls to the wall: How acoustic information from a ball in motion guides interceptive movement in people with Parkinson’s disease

Previous research has shown that Parkinson's disease (PD) patients can increase the speed of their movement when catching a moving ball compared to when reaching for a static ball (Majsak et al., 1998). A recent model proposed by Redgrave et al. (2010) explains this phenomenon with regard to the dichotomic organization of motor loops in the basal ganglia circuitry and the role of sensory micro-circuitries in the control of goal-directed actions. According to this model, external visual information that is relevant to the required movement can induce a switch from a habitual control of movement toward an externally-paced, goal-directed form of guidance, resulting in augmented motor performance (Bienkiewicz et al., 2013). In the current study, we investigated whether continuous acoustic information generated by an object in motion can enhance motor performance in an arm reaching task in a similar way to that observed in the studies of Majsak et al. (1998, 2008). In addition, we explored whether the kinematic aspects of the movement are regulated in accordance with time to arrival information generated by the ball's motion as it reaches the catching zone. A group of 7 idiopathic PD (6 male, 1 female) patients performed a ball-catching task where the acceleration (and hence ball velocity) was manipulated by adjusting the angle of the ramp. The type of sensory information (visual and/or auditory) specifying the ball's arrival at the catching zone was also manipulated. Our results showed that patients with PD demonstrate improved motor performance when reaching for a ball in motion, compared to when stationary. We observed how PD patients can adjust their movement kinematics in accordance with the speed of a moving target, even if vision of the target is occluded and patients have to rely solely on auditory information. We demonstrate that the availability of dynamic temporal information is crucial for eliciting motor improvements in PD. Furthermore, these effects appear independent from the sensory modality through-which the information is conveyed. 

Mitochondrial translation initiation factor 3 polymorphism and Parkinson's disease

Mitochondrial dysfunction has been proposed to play a role in the pathogenesis of Parkinson s disease (PD) Supportive of this hypothesis several genetic variants that regulate mitochondrial function and homeostasis have been described to alter PD susceptibility A recent report demonstrated association of a single nucleotide polymorphism in the mitochondrial translation initiation factor 3 (MTIF3) gene with PD risk The protein encoded by this nuclear gene is essential for initiation complex formation on the mitochondrial 55S ribosome and regulates translation of proteins within the mitochondria Changes in the function or expression of the MTIF3 protein may result in altered mitochondrial function ATP production or formation of reactive oxygen species thereby affecting susceptibility to PD We examined the association of rs7669 with sporadic PD in three Caucasian case control series (n = 2434) A significant association was observed in the largest series (Norwegian n = 1650) when comparing CC vs CT/TT genotypes with the Irish and US series having a similar but non-significant trend The combined series also revealed an association with risk of PD (P = 0 01) supporting the possible involvement of this gene in PD etiology Published by Elsevier Ireland Ltd

Clinical traits of LRRK2-associated parkinson's disease in ireland: a link between familial and idiopathic PD

The role of genetics in parkinsonism has been confirmed over the last decade with the identification of genetic variation in seven genes, which are causative in familial forms of the disorder. A number of pathogenic mutations have been identified in the latest gene LRRK2, with a Gly2019Ser amino acid substitution identified in two siblings and one patient with idiopathic Parkinson's disease from Ireland. The clinical features resemble the idiopathic variant with a tremor predominant clinical picture shared by the siblings, slow progression of symptoms, and no observation of cognitive disturbance in all. The family and the sporadic individual were apparently not related and originated from different regions of Ireland, although haplotype analysis does suggest they share a common founder. The influence of the G2019S substitution on protein function and disease phenotype has yet to be fully resolved, but its elucidation will undoubtedly further our understanding of the mechanisms underlying Parkinson's disease.

Inhibitors of alpha-synuclein oligomerization and toxicity: a future therapeutic strategy for Parkinson's disease and related disorders.

An abundance of genetic, histopathological, and biochemical evidence has implicated the neuronal protein, alpha-synuclein (alpha-syn) as a key player in the development of several neurodegenerative diseases, the so-called synucleinopathies, of which Parkinson's disease (PD) is the most prevalent. Development of disease appears to be linked to events that increase the intracellular concentration of alpha-syn or cause its chemical modification, either of which can accelerate the rate at which it forms aggregates. Examples of such events include increased copy number of genes, decreased rate of degradation via the proteasome or other proteases, or altered forms of alpha-syn, such as truncations, missense mutations, or chemical modifications by oxidative reactions. Aggregated forms of the protein, especially newly formed soluble aggregates, are toxic to cells, so that one therapeutic strategy would be to reduce the rate at which such oligomerization occurs. We have therefore designed several peptides and also identified small molecules that can inhibit alpha-syn oligomerization and toxicity in vitro. These compounds could serve as lead compounds for the design of new drugs for the treatment of PD and related disorders in the future.