Mechanisms of LRRK2-Mediated Neurodegeneration

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent the most common cause of familial Parkinson's disease (PD), whereas common variation at the LRRK2 locus is associated with an increased risk of idiopathic PD. Considerable progress has been made toward understanding the biological functions of LRRK2 and the molecular mechanisms underlying the pathogenic effects of disease-associated mutations. The development of neuronal culture models and transgenic or viral-based rodent models have proved useful for identifying a number of emerging pathways implicated in LRRK2-dependent neuronal damage, including the microtubule network, actin cytoskeleton, autophagy, mitochondria, vesicular trafficking, and protein quality control. However, many important questions remain to be posed and answered. Elucidating the molecular mechanisms and pathways underlying LRRK2-mediated neurodegeneration is critical for the identification of new molecular targets for therapeutic intervention in PD. In this review we discuss recent advances and unanswered questions in understanding the pathophysiology of LRRK

Oxidative modifications, mitochondrial dysfunction, and impaired protein degradation in Parkinson's disease: how neurons are lost in the Bermuda triangle

While numerous hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of neurodegenerative diseases, the theory of oxidative stress has received considerable support. Although many correlations have been established and encouraging evidence has been obtained, conclusive proof of causation for the oxidative stress hypothesis is lacking and potential cures have not emerged. Therefore it is likely that other factors, possibly in coordination with oxidative stress, contribute to neuron death. Using Parkinson's disease (PD) as the paradigm, this review explores the hypothesis that oxidative modifications, mitochondrial functional disruption, and impairment of protein degradation constitute three interrelated molecular pathways that execute neuron death. These intertwined events are the consequence of environmental exposure, genetic factors, and endogenous risks and constitute a "Bermuda triangle" that may be considered the underlying cause of neurodegenerative pathogenesis

Differential monocular vs. binocular pupil responses from melanopsin-based photoreception in patients with anterior ischemic optic neuropathy.

We examined the effect of anterior ischemic optic neuropathy (AION) on the activity of intrinsically photosensitive retinal ganglion cells (ipRGCs) using the pupil as proxy. Eighteen patients with AION (10 unilateral, 8 bilateral) and 29 age-matched control subjects underwent chromatic pupillometry. Red and blue light stimuli increasing in 0.5 log steps were presented to each eye independently under conditions of dark and light adaptation. The recorded pupil contraction was plotted against stimulus intensity to generate scotopic and photopic response curves for assessment of synaptically-mediated ipRGC activity. Bright blue light stimuli presented monocularly and binocularly were used for melanopsin activation. The post-stimulus pupil size (PSPS) at the 6th second following stimulus offset was the marker of intrinsic ipRGC activity. Finally, questionnaires were administered to assess the influence of ipRGCs on sleep. The pupil response and PSPS to all monocularly-presented light stimuli were impaired in AION eyes, indicating ipRGC dysfunction. To binocular light stimulation, the PSPS of AION patients was similar to that of controls. There was no difference in the sleep habits of the two groups. Thus after ischemic injury to one or both optic nerves, the summated intrinsic ipRGC activity is preserved when both eyes receive adequate light exposure

Surgical Management of Epiretinal Membrane

Epiretinal membranes (ERMs) are contractile membranes that occur on the inner surface of the retina and can lead to significant visual impairment when located at the central retina. Recent advances in vitreoretinal surgery have greatly improved the safety and efficacy of microsurgical intervention at the retinal surface level. Today, vitrectomy and membrane peels are considered the treatment of choice for most patients with ERMs that create significant visual symptoms. Nevertheless, possible complications such as accelerated cataract formation, recurrence of ERM and retinal detachment may withhold the choice of surgical intervention. Additionally, in some cases, simple observation may be advised. In view of surgery, controversies regarding techniques such as those related to an internal limiting membrane peel and the use of dye still exist. In this chapter, we cover current surgical techniques for ERM removal, their expected results, possible complications, as well as a guide for possible case selection

Muscle loading effects on bone parameters in the oim mouse model [abstract]

Faculty Mentor: Dr. Charlotte Phillips, BiochemistryAbstract only availablePrevious studies have shown that mechanical loading on the skeleton acts as an anabolic stimulus, inducing changes in bone geometry, bone mineral density, and mechanical properties. Increases in these properties may improve bone quality as seen by increased bone density following sustained physical activity, and the increase may be due to increased muscle contraction. Much data exists on the effects of unloading on the skeleton, but data regarding the effects of loading is limited. This study is aimed at examining the effects of loading on the skeleton of the oim mouse model. The oim mouse model produces defective type I collagen, the most abundant structural protein in the body. The oim mouse has a phenotype similar to human type III human osteogenesis imperfecta (OI), including fractures, cortical thinning, and bowing of long bones. Current therapies for OI have been marginally successful and can be painful and invasive with significant recovery times. Data from this study may aid in development of non-invasive treatments via target exercise and muscle training for OI, and other bone diseases such as osteoporosis. This project served as a pilot study to determine if current methods are sensitive enough to detect changes that occur due to muscle loading. Mice were anesthetized and the gastrocnemius muscle removed to impose mechanical overload on the plantaris and soleus muscles. The mice resumed activity for three weeks before being euthanized and the leg bones removed. The bones were subject to microCT to obtain geometric parameters before undergoing torsional loading to failure to assess bone biomechanics. The remaining muscles were examined for histological differences, and their collagen content determined using a hydroxyproline assay. Data thus far confirms that our methodology will detect changes in both muscle and bone, and future work will determine if muscle loading improves bone quality

Mechanisms of LRRK2-Mediated Neurodegeneration

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent the most common cause of familial Parkinson's disease (PD), whereas common variation at the LRRK2 locus is associated with an increased risk of idiopathic PD. Considerable progress has been made toward understanding the biological functions of LRRK2 and the molecular mechanisms underlying the pathogenic effects of disease-associated mutations. The development of neuronal culture models and transgenic or viral-based rodent models have proved useful for identifying a number of emerging pathways implicated in LRRK2-dependent neuronal damage, including the microtubule network, actin cytoskeleton, autophagy, mitochondria, vesicular trafficking, and protein quality control. However, many important questions remain to be posed and answered. Elucidating the molecular mechanisms and pathways underlying LRRK2-mediated neurodegeneration is critical for the identification of new molecular targets for therapeutic intervention in PD. In this review we discuss recent advances and unanswered questions in understanding the pathophysiology of LRRK2

Impact of the influenza A(H1N1) 2009 pandemic to the 17-25 year age group and to the students of the Medical School, Aristotle University of Thessaloniki

Introduction: In 2009 a novel A(H1N1) influenza virus emerged and caused a pandemic. The scope of this study was to identify the impact of the pandemic to the 17-25 year age group and to normal University function.Methods: a) Epidemiological data was obtained from the National Influenza Center for northern Greece, regarding the 17-25 age group. b) Absence records from the first semester of 2008-2009 and 2009-2010 were obtained from the School of Medicine, Aristotle University of Thessaloniki and a questionnaire was given to 100 medical students.Results and discussion: a) Two pandemic waves were identified; the first was during weeks 27-35 and the second during weeks 43-52.Of the 4949 examined samples, 1632 were confirmed pandemic H1N1 2009 infections (33%), and 362 (22%) belonged to the 17-25 age group. Of the latest, 53% were male and 47% were female. Most infections belonging to this group were mild, and developed influenza like illness (ILI) symptoms. Only 19% developed pneumonia or other complications and 2 were fatal. 4% was vaccinated against influenza and 2% against S. pneumoniae. Only 7% received Tamiflu treatment. 9% noted a travel history related to their infection. b) The second wave was synchronous with the 1st University Semester. However, no statistical difference between absence levels during 2008-2009 and 2009-2010 was identified and no students had reported ILI symptoms.Conclusively, whereas the 17-25 age group was indeed of the mostly affected from the pandemic, it seems that unexpectedly there was no impact to normal University function