Hf Tse

Human neuronal uncoupling proteins 4 and 5 (UCP4 and UCP5): structural properties, regulation, and physiological role in protection against oxidative stress and mitochondrial dysfunction

Uncoupling proteins (UCPs) belong to a large family of mitochondrial solute carriers 25 (SLC25s) localized at the inner mitochondrial membrane. UCPs transport protons directly from the intermembrane space to the matrix. Of five structural homologues (UCP1 to 5), UCP4 and 5 are principally expressed in the central nervous system (CNS). Neurons derived their energy in the form of ATP that is generated through oxidative phosphorylation carried out by five multiprotein complexes (Complexes I–V) embedded in the inner mitochondrial membrane. In oxidative phosphorylation, the flow of electrons generated by the oxidation of substrates through the electron transport chain to molecular oxygen at Complex IV leads to the transport of protons from the matrix to the intermembrane space by Complex I, III, and IV. This movement of protons to the intermembrane space generates a proton gradient (mitochondrial membrane potential; MMP) across the inner membrane. Complex V (ATP synthase) uses this MMP to drive the conversion of ADP to ATP. Some electrons escape to oxygen‐forming harmful reactive oxygen species (ROS). Proton leakage back to the matrix which bypasses Complex V resulting in a major reduction in ROS formation while having a minimal effect on MMP and hence, ATP synthesis; a process termed “mild uncoupling.” UCPs act to promote this proton leakage as means to prevent excessive build up of MMP and ROS formation. In this review, we discuss the structure and function of mitochondrial UCPs 4 and 5 and factors influencing their expression. Hypotheses concerning the evolution of the two proteins are examined. The protective mechanisms of the two proteins against neurotoxins and their possible role in regulating intracellular calcium movement, particularly with regard to the pathogenesis of Parkinsons disease are discussed.

LRRK2 R1441G mice are more liable to dopamine depletion and locomotor inactivity

Mutations in leucine‐rich repeat kinase 2 (LRRK2) pose a significant genetic risk in familial and sporadic Parkinsons disease (PD). R1441 mutation (R1441G/C) in its GTPase domain is found in familial PD. How LRRK2 interacts with synaptic proteins, and its role in dopamine (DA) homeostasis and synaptic vesicle recycling remain unclear.

Uncoupling Protein-4 (UCP4) Increases ATP Supply by Interacting with Mitochondrial Complex II in Neuroblastoma Cells

Mitochondrial uncoupling protein-4 (UCP4) protects against Complex I deficiency as induced by 1-methyl-4-phenylpyridinium (MPP+), but how UCP4 affects mitochondrial function is unclear. Here we investigated how UCP4 affects mitochondrial bioenergetics in SH-SY5Y cells. Cells stably overexpressing UCP4 exhibited higher oxygen consumption (10.1%, p<0.01), with 20% greater proton leak than vector controls (p<0.01). Increased ATP supply was observed in UCP4-overexpressing cells compared to controls (p<0.05). Although state 4 and state 3 respiration rates of UCP4-overexpressing and control cells were similar, Complex II activity in UCP4-overexpressing cells was 30% higher (p<0.05), associated with protein binding between UCP4 and Complex II, but not that of either Complex I or IV. Mitochondrial ADP consumption by succinate-induced respiration was 26% higher in UCP4-overexpressing cells, with 20% higher ADP:O ratio (p<0.05). ADP/ATP exchange rate was not altered by UCP4 overexpression, as shown by unchanged mitochondrial ADP uptake activity. UCP4 overexpression retained normal mitochondrial morphology in situ, with similar mitochondrial membrane potential compared to controls. Our findings elucidate how UCP4 overexpression increases ATP synthesis by specifically interacting with Complex II. This highlights a unique role of UCP4 as a potential regulatory target to modulate mitochondrial Complex II and ATP output in preserving existing neurons against energy crisis.

Cancer patients are at increased risk of recurrent stroke and cardiovascular mortality

WCN 2013 No: 1538 Topic: 3 — Stroke Stroke awareness in Munich and Moscow Y. Fris, P. Kamchatnov, R. Kalla. The Russian National Research Medical University, Moscow, Russia; Ludwig–Maximilians-University Munich, Klinikum Groshadern, Munich, Germany Background: Different data of public stroke awareness in several researches may result from different methods of investigations. Objectives: We aimed to compare the stroke awareness among patients in Moscow and Munich. Material andmethods: 180 patients in Moscow (48% female, mean age 63.09 ± 13.83) and 180 patients in Munich (47.8% female, mean age 61.12 ± 14) hospitals, divided into three groups (after stroke, high risk of stroke and without risk of stroke) answered 33 questions, including 4 open-ended questions about stroke symptoms (SS) and risk factors (RF). Results: In group of patients without risk of stroke the difference in number of SS named was not significant. In group of patients with high risk of stroke the awareness of SS (1.96 ± 1.28 in Munich and 1.03 ± 1.07 in Moscow, p = 0.000) and the awareness of stroke RF (2.25 ± 1.29 in Munich and 1.34 ± 1.2 in Moscow, p = 0.000) were better among patients in Munich. In group of patients with stroke in anamnesis the awareness of SS (2.08 ± 0.99 inMunich and 1.25 ± 0.89 in Moscow, p = 0.000) was also better among patients in Munich. The difference in awareness of stroke RF in this group was not significant. The direct dialogue with the doctor and specialized brochure was named as most preferable forms of increasing the knowledge of risk factors and stroke symptoms. Conclusion: The educational activities inMoscow should be focused on patients with high risk of stroke and should increase the recognition of stroke onset and highlight the importance of early hospitalization. doi:10.1016/j.jns.2013.07.814 Abstract — WCN 2013 No: 1550 Topic: 3 — Stroke Arterial CNS involvement in Behcets disease WCN 2013 No: 1550 Topic: 3 — Stroke Arterial CNS involvement in Behcets disease G. Akman-Demir, E. Shugaiv, M. Kurtuncu, M. Mutlu, N. YesilotBarlas, E. Tuzun, O. Coban, S. Bahar. Department of Neurology, Istanbul Bilim University Medical School, Turkey; Department of Neurology, Istanbul University Faculty of Medicine, Turkey; Department of Neurology, Istanbul University School of Medicine, Istanbul, Turkey Background and objective: Although Behcet disease (BD) tends to involve vascular structures, the incidence of arterial involvement is far behind that of venous involvement. In this study, we evaluated all the cases with BD and arterial CNS involvement. Methods: All the files of Neuro-Behcet outpatient clinic of Istanbul Medical Faculty were retrospectively evaluated. Demographical findings, clinical characteristics and radiological findings were evaluated. Results: Between 1984 and 2011 there were 18 cases with BD and cranial arterial involvement out of 400 patients with neurological involvement. 4were female and 14weremale (M:F = 3.5). Their age at arterial CNS involvement ranged between 25 and 64 years (median: 42; 42.5 ± 11.7). 15 had presented with acute hemiparesis/hemiplegia, accompanied by aphasia in two, ataxia in one, crossed brainstem syndrome in two patients. One patient had an asymptomatic intracranial aneurysm. One patient presented with seizures due to ACA infarct, and one patient presented with multiple cranial neuropathies due to external carotid aneurysm. One of the female patients had an underlying rheumatic mitral stenosis, and 3 patients were over age 50 which may suggest that stroke may not be directly associated to BD in those 4 cases. In 2 patients vasculitic involvement could be shown on angiography. In the remaining patients no other etiologies were found. Conclusions: Arterial CNS involvement is rarely seen in BD. A minority of those cases could be shown to have vasculitis. Other etiological factors unrelated to BD should be sought exclusively in such cases before attributing the stroke to BD. doi:10.1016/j.jns.2013.07.815 Abstract — WCN 2013 No: 1572 Topic: 3 — Stroke Cancer patients are at increased risk of recurrent stroke and cardiovascular mortality WCN 2013 No: 1572 Topic: 3 — Stroke Cancer patients are at increased risk of recurrent stroke and cardiovascular mortality K.K. Lau, Y.-K. Wong, K.-H. Chan, K.-C. Teo, S.F.-K. Hon, W. Mak, R.T.-F. Cheung, S.-L. Ho, L.S.-W. Li, H.-F. Tse, C.-W. Siu. The University of Hong Kong, Hong Kong, Hong Kong Special Administrative Region Background: Cancer patients are at increased risk of cardiovascular and cerebrovascular events. However, the risk of recurrent stroke or cardiovascular mortality amongst cancer patients with stroke is currently unknown. Objective: To determine the risk of recurrent stroke and cardiovascular mortality in cancer patients with ischemic stroke. Patients and methods: This is a single center, observational study comparing the clinical characteristics and outcome of 58 ischemic stroke patients with cancer to 1047 ischemic stroke patients without cancer recruited from 2004 to 2008. Mean follow-up period was 76 ± 18months. Primary endpoint was recurrent stroke and secondary endpoint was cardiovascular mortality. Results: The three most common malignancies were breast (17%), colorectal (14%) and nasopharynx (13%). 26% of cancer subjects had active malignancy and 7% had metastatic disease. 22 patients with cancer (38%, 13.94 per 100 patient-years) and 219 patients without cancer (21%, 4.65 per 100 patient-years) developed a recurrent stroke (p b 0.01). 13 patients with cancer (22%, 4.3 per 100 patientyears) and 143 patients without cancer (14%, 2.35 per 100 patientyears, p = 0.08) died due to cardiovascular causes. After adjusting for age, gender, cardiovascular risk factors and co-morbidities, cancer was an independent predictor for recurrent stroke (HR 2.68; 95% CI: 1.58 to 4.54, p b 0.01) and cardiovascular mortality (HR 2.17; 95% CI: 1.12 to 4.22, p= 0.02). Conclusion: Stroke patients with underlying cancer are at increased risk of developing recurrent stroke and cardiovascular mortality. doi:10.1016/j.jns.2013.07.816 Abstracts / Journal of the Neurological Sciences 333 (2013) e152–e214 e204