G2019S LRRK2 Increases Stress Susceptibility Through Inhibition of DAF-16 Nuclear Translocation in a 14-3-3 Associated-Manner in Caenorhabditis elegans

Mutations in leucine-rich repeat kinase 2 (LRRK2) are common causes of familial Parkinson’s disease (PD). Oxidative stress plays a key role in the pathogenesis of PD. Mutations in LRRK2 have been shown to increase susceptibility to oxidative stress. To explore mechanisms underlying susceptibility to oxidative stress in LRRK2 mutants, we generated stable Caenorhabditis elegans (C. elegans) strains in which human LRRK2 proteins including wild type LRRK2 (WT), G2019S LRRK2 (G2019S), and G2019S-D1994A kinase-dead LRRK2 (KD) were expressed in all neurons. Human 14-3-3 β was injected into LRRK2 transgenic worms to allow co-expression of 14-3-3 β and LRRK2 proteins. We found that G2019S transgenic worms had increased sensitivity to stress (heat and juglone treatment) and impaired stress-induced nuclear translocation of DAF-16. In addition, G2019S inhibited ftt2 (a 14-3-3 gene homolog in C. elegans) knockdown-associated nuclear translocation of DAF-16. Comparably, overexpression of human 14-3-3 β could attenuate G2019S-associated toxicity in response to stress and rescued G2019S-mediated inhibition of sod-3 and dod-3 expression. Taken together, our study provides evidence suggesting that 14-3-3-associated inhibition of DAF-16 nuclear translocation could be a mechanism for G2019S LRRK2-induced oxidative stress and cellular toxicity. Our findings may give a hint that the potential of 14-3-3 proteins as neuroprotective targets in PD patients carrying LRRK2 mutations

Differentiating Non-Motor Symptoms in Parkinson's Disease from Controls and Hemifacial Spasm

10.1371/journal.pone.0049596PLoS ONE82

Challenges in the management of a patient with Cowden syndrome: case report and literature review

We would like to present a patient with a classical phenotype of a rare disorder - Cowden syndrome, its diagnostics and management challenges. A breast surgeon has to be aware of this rare condition when treating a patient with breast manifestations of Cowden syndrome and has to refer the patient to a clinical geneticist for further evaluation. Sequencing of the PTEN gene showed the Asp24Gly mutation. According to the latest literature data, the lifetime risk of breast cancer for Cowden syndrome patients is 81% and surgery is a justified option to reduce the risk of breast cancer. Bilateral risk-reducing mastectomy with immediate reconstruction was performed to eliminate further risk of breast cancer. 3 years after the risk-reducing breast surgery the patient is satisfied with the outcome. This is to our best knowledge the first reported Cowden syndrome case with follow-up data after risk-reducing measures have been taken

Impulse control behaviours in a Malaysian Parkinson’s disease population

Background: Impulse control behaviours are repetitive and excessive activities that may be sub-syndromal and not fulfill the criteria for impulse control disorder. These activities have potential to negatively impact on the daily lives of sufferers. We conducted a study to investigate the prevalence of impulse control behaviors and its associated features in Parkinson’s disease in our population. Methods: We conducted a prospective cross-sectional study on consecutive patients attending neurology clinic. Inclusion criteria include idiopathic Parkinson’s disease patients with Hoehn & Yahr stage I-IV. Eighty patients were enrolled and screened for impulse control behaviors using the Questionnaire for Impulsive-Compulsive Disorder for Parkinson’s disease (QUIP). Results: Prevalence of impulse control behaviors among our cohort was 11.3%; the features significantly associated with it were higher level of education (p=0.02), advanced stage of disease (p=0.03) and higher levodopa dosage (p= 0.01). The commonest impulse control behavior in our cohort was compulsive medication use (7.5%), followed by hobbyism (6.3%), hypersexuality (5%), compulsive buying (3.75%), punding (2.5%), walkabout (2.5%), compulsive eating (1.25%) and pathological gambling (1.3%). Conclusions: There is an association between impulse control behavior and higher levodopa dosage in a study on patients with Parkinson’s disease in Malaysia. We also found a low prevalence of pathological gambling as compared to studies performed in the West

Non-Motor and Motor Features in LRRK2 Transgenic Mice

10.1371/journal.pone.0070249PLoS ONE87-POLN

Deletion of the WD40 Domain of LRRK2 in Zebrafish Causes Parkinsonism-Like Loss of Neurons and Locomotive Defect

LRRK2 plays an important role in Parkinson's disease (PD), but its biological functions are largely unknown. Here, we cloned the homolog of human LRRK2, characterized its expression, and investigated its biological functions in zebrafish. The blockage of zebrafish LRRK2 (zLRRK2) protein by morpholinos caused embryonic lethality and severe developmental defects such as growth retardation and loss of neurons. In contrast, the deletion of the WD40 domain of zLRRK2 by morpholinos targeting splicing did not induce severe embryonic developmental defects; rather it caused Parkinsonism-like phenotypes, including loss of dopaminergic neurons in diencephalon and locomotion defects. These neurodegenerative and locomotion defects could be rescued by over-expressing zLRRK2 or hLRRK2 mRNA. The administration of L-dopa could also rescue the locomotion defects, but not the neurodegeneration. Taken together, our results demonstrate that zLRRK2 is an ortholog of hLRRK2 and that the deletion of WD40 domain of zLRRK2 provides a disease model for PD