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1.5.2 ERK PATHWAY IS INVOLVED IN SNCA INDUCED MITOCHONDRIAL DYNAMIC DISORDERS BY REGULATING DLP1
Monday, 12 December 2011 / Parkinsonism and Related Disorders 18S2 (2012) S1–S79
a re-grouping of diseases according to the expected pathology. The clinical syndrome of PD can now be classified into forms with and without alpha-synuclein pathology. DLB and PDD are synucleinopathies, and MSA shows alpha-synuclein pathology with glial inclusions. ADHD symptoms commonly occur in persons that will subsequently develop DLB. A similar phenomenon may be the early personality changes and frontotemporal atrophy in patients with SNCA multiplication. RLS is not known to have alpha-synuclein pathology, but as PD and ADHD, involves a hypodopaminergic state. Furthermore, PD and RLS co-occur in families in a way that suggests common inheritance. A proportion of patients with ET have brainstem Lewy body pathology. Gaucher’s disease and other lysosomal storage disorders also have alpha-synuclein pathology. Alpha-synuclein is a naturally unfolded protein. Non-fibrillar oligomeres may be the toxic species, and Lewy body formation may in fact be protective. Inhibiting alpha-synuclein toxicity seems to be an attractive novel treatment strategy and several approaches are being developed. When such treatments become available, clinicians will need to be familiar with the clinical features that distinguish the synucleinopathies from their look-alikes. Chinese Session Progress of PD Research Chairpersons: Yan Chen, China; Zhuolin Liu, China
08:30–10:00
1.5.1 GENETICS B. Tang. Department of Neurology, Xiangya Hospital, Central South University, Changsha, China Objective: A systemic evaluation of the independent and combined effects of Rep1, rs11931074, rs356165in SNCA gene; G2385R, R1628P in LRRK2 gene; rs242562, rs2435207 in MAPT gene and L444P in GBA gene; rs3129882, rs3117098 in HLA-DR gene; rs4698412, rs11931532 in BST1 gene; rs823156, rs11240572 in PARK16; rs11248051, rs1564282 in PARK17 on the sporadic PD patients and normal controls in Chinese population was done to discuss that multiple genes may interact with one another. Methods: Gene mutation analysis of SNCA, LRRK2, MAPT , GBA, HLA-DR, BST1, PARK16, PARK17 were carried out by polymerase chain reaction (PCR) combined with DNA direct sequencing in 1011 sporadic PD patients and 1016 normal controls to discuss the interactions of multiple genes. Results: Rep1, rs356165, rs11931074 in SNCA gene, G2385R in LRRK2 gene, rs4698412 in BST1 gene, rs1564282 in PARK17, L444P in GBA gene were associated with PD with adjustment of sex and age (P < 0.05) in the analysis of sixteen variants. PD risk was increased when Rep1 and rs11931074, rs356165, Rep1 and G2385R, rs356165 and G2385R were combined for association analysis. In addition, PD risk increased cumulatively with the increasing number of variants (OR for carrying 4 variants: 23.259). Conclusion: In this study, we confirm that Rep1, rs356165, rs11931074 in SNCA gene, G2385R in LRRK2 gene, rs4698412 in BST1 gene, rs1564282 in PARK17, L444P in GBA gene have an independent and combined significant association with PD. L444P in GBA gene was speculated as an independent risk factor. SNPs in four genes have a cumulative effect with PD. 1.5.2 ERK PATHWAY IS INVOLVED IN SNCA INDUCED MITOCHONDRIAL DYNAMIC DISORDERS BY REGULATING DLP1 J. Liu, Y.-X. Gui, S. Chen. Ruijin Hospital, Shanghai, China Compounding evidence suggests that alpha-synuclein (SNCA) plays an important role in the pathogenesis of Parkinson’s disease (PD). Mitochondria are highly dynamic organelles that undergo fusion and fission processes, the imbalance of which has been viewed as a key trigger for PD. However, the underlying relationship between SNCA and mitochondrial dynamics remain unclear. Our
S3
study demonstrated that SNCA overexpression not only altered mitochondrial morphology, but also increased the translocation of mitochondrial fission protein dynamin-like protein 1 (DLP1). In order to further investigate the mechanism of SNCA’s effect on mitochondrial dynamics, one proteomic technique, stable isotope labeling of amino acid in cell cultures (SILAC), was used. The SILAC proteomic analysis identified 452 proteins, of which 66 proteins were involved in signal transduction process. Of those, one signal pathway, the extracellular signal-regulated kinase (ERK), was confirmed to be involved in the regulation of DLP1 and SNCAmediated neurotoxicity. Finally, additional results demonstrated that SNCA inducing both mitochondrial dynamic disorders and neurotoxicity could be ameliorated by curcumin through ERK inhibition, which implied that the agent could be used to prevent and treat PD in future. 1.5.3 METABOLIC NETWORKING IN CHINESE PATIENTS WITH PARKINSON’S DISEASE IN VARIOUS HOEHN & YAHR STAGES J. Wang1 , C. Zuo2 , P. Wu2 , H. Zhang2 , Y. Guan2 , J. Wu1 , Z. Ding1 , Y. Jiang1 . 1 Neurology, 2 PET Center, Huashan Hospital, Fudan University, Shanghai, China Objective: To analyze the pattern of the Parkinson’s diseaserelated spatial covariance pattern (PDRP) in Chinese patients with Parkinson’s disease at various Hoehn & Yahr stages, and to assess the correlation between the PDRP expression and severity of UPDRS motor score in those patients. Methods: 18 cases of healthy control (55.6±8.7 yrs, 6 females and 12 males) and 18 cases of PD patients (57.2±9.0 yrs, 8 females and 10 males) participated in the study. Among those patients, 4 cases are at HY stage I, 5 cases II, 5 cases III, 3 cases IV, and 1 case V. The UPDRS ratings were taken 12 h off any other medications. 5 mCi 18F-FDG was intravenous injected and The PET scans were performed with an ECAT EXACT HR tomography in 3D mode. Results: The PDRP was expressed in Chinese PD patients as the same pattern as previously reported, which was characterized by lentiform, thalamic and cerebellar hypermetabolism covarying with metabolic reductions in the lateral premotor and supplementary motor area. PDRP value was 1.48±0.74 in PD group compared with −0.06±0.43 in control group. The network activity in PD patients was significantly correlated to UPDRS motor subscores Conclusion: The pattern of PDRP expressed in Chinese PD patients was consistent with previous literatures, and its value was correlated to severity of motor symptoms. It might be served as a potential biomarker for monitoring the severity of PD, which awaits confirmation from more longitudinal studies in the future. 1.5.4 BIOMARKERS FOR EARLY DIAGNOSIS OF PD P. Xu. Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China Two novel mutations of Nurr1 were found in PD patients. The Nurr1 mRNA levels of PD patients decreased by 58.6% versus controls. Early-onset PD had lower Nurr1 mRNA levels than late-onset PD. As compared to control, the expression level of Nurr1 in early-onset PD was 71.8% lower while the late-onset PD was 54.9% lower. Stratified analysis showed that all subgroups of PD (grouped according to the Hoehn and Yahr scales) had lower Nurr1 mRNA levels and the subgroup (2≤H&Y Scales <3) is the most significant one. It’s reported that Nurr1 gene could activate the transcript of several downstream genes involved in dopamine metabolism such as AAD, RXRg, Akt etc. RXR is the primary subunit receptor of Nurr1 while Akt play an important role in anti-apoptosis. The half-time period (T1/2) of Nurr1 mRNA is 12 hrs while the variant Nurr1-c is 6 hrs. Nurr1 activator SH1 could lead to a 6-fold increase of TH gene and a 2.8-fold increase of DAT gene in SH-SY5Y cells. In addition, we found that the mean serum uric acid (UA) level of PD patients was
a re-grouping of diseases according to the expected pathology. The clinical syndrome of PD can now be classified into forms with and without alpha-synuclein pathology. DLB and PDD are synucleinopathies, and MSA shows alpha-synuclein pathology with glial inclusions. ADHD symptoms commonly occur in persons that will subsequently develop DLB. A similar phenomenon may be the early personality changes and frontotemporal atrophy in patients with SNCA multiplication. RLS is not known to have alpha-synuclein pathology, but as PD and ADHD, involves a hypodopaminergic state. Furthermore, PD and RLS co-occur in families in a way that suggests common inheritance. A proportion of patients with ET have brainstem Lewy body pathology. Gaucher’s disease and other lysosomal storage disorders also have alpha-synuclein pathology. Alpha-synuclein is a naturally unfolded protein. Non-fibrillar oligomeres may be the toxic species, and Lewy body formation may in fact be protective. Inhibiting alpha-synuclein toxicity seems to be an attractive novel treatment strategy and several approaches are being developed. When such treatments become available, clinicians will need to be familiar with the clinical features that distinguish the synucleinopathies from their look-alikes. Chinese Session Progress of PD Research Chairpersons: Yan Chen, China; Zhuolin Liu, China
08:30–10:00
1.5.1 GENETICS B. Tang. Department of Neurology, Xiangya Hospital, Central South University, Changsha, China Objective: A systemic evaluation of the independent and combined effects of Rep1, rs11931074, rs356165in SNCA gene; G2385R, R1628P in LRRK2 gene; rs242562, rs2435207 in MAPT gene and L444P in GBA gene; rs3129882, rs3117098 in HLA-DR gene; rs4698412, rs11931532 in BST1 gene; rs823156, rs11240572 in PARK16; rs11248051, rs1564282 in PARK17 on the sporadic PD patients and normal controls in Chinese population was done to discuss that multiple genes may interact with one another. Methods: Gene mutation analysis of SNCA, LRRK2, MAPT , GBA, HLA-DR, BST1, PARK16, PARK17 were carried out by polymerase chain reaction (PCR) combined with DNA direct sequencing in 1011 sporadic PD patients and 1016 normal controls to discuss the interactions of multiple genes. Results: Rep1, rs356165, rs11931074 in SNCA gene, G2385R in LRRK2 gene, rs4698412 in BST1 gene, rs1564282 in PARK17, L444P in GBA gene were associated with PD with adjustment of sex and age (P < 0.05) in the analysis of sixteen variants. PD risk was increased when Rep1 and rs11931074, rs356165, Rep1 and G2385R, rs356165 and G2385R were combined for association analysis. In addition, PD risk increased cumulatively with the increasing number of variants (OR for carrying 4 variants: 23.259). Conclusion: In this study, we confirm that Rep1, rs356165, rs11931074 in SNCA gene, G2385R in LRRK2 gene, rs4698412 in BST1 gene, rs1564282 in PARK17, L444P in GBA gene have an independent and combined significant association with PD. L444P in GBA gene was speculated as an independent risk factor. SNPs in four genes have a cumulative effect with PD. 1.5.2 ERK PATHWAY IS INVOLVED IN SNCA INDUCED MITOCHONDRIAL DYNAMIC DISORDERS BY REGULATING DLP1 J. Liu, Y.-X. Gui, S. Chen. Ruijin Hospital, Shanghai, China Compounding evidence suggests that alpha-synuclein (SNCA) plays an important role in the pathogenesis of Parkinson’s disease (PD). Mitochondria are highly dynamic organelles that undergo fusion and fission processes, the imbalance of which has been viewed as a key trigger for PD. However, the underlying relationship between SNCA and mitochondrial dynamics remain unclear. Our
S3
study demonstrated that SNCA overexpression not only altered mitochondrial morphology, but also increased the translocation of mitochondrial fission protein dynamin-like protein 1 (DLP1). In order to further investigate the mechanism of SNCA’s effect on mitochondrial dynamics, one proteomic technique, stable isotope labeling of amino acid in cell cultures (SILAC), was used. The SILAC proteomic analysis identified 452 proteins, of which 66 proteins were involved in signal transduction process. Of those, one signal pathway, the extracellular signal-regulated kinase (ERK), was confirmed to be involved in the regulation of DLP1 and SNCAmediated neurotoxicity. Finally, additional results demonstrated that SNCA inducing both mitochondrial dynamic disorders and neurotoxicity could be ameliorated by curcumin through ERK inhibition, which implied that the agent could be used to prevent and treat PD in future. 1.5.3 METABOLIC NETWORKING IN CHINESE PATIENTS WITH PARKINSON’S DISEASE IN VARIOUS HOEHN & YAHR STAGES J. Wang1 , C. Zuo2 , P. Wu2 , H. Zhang2 , Y. Guan2 , J. Wu1 , Z. Ding1 , Y. Jiang1 . 1 Neurology, 2 PET Center, Huashan Hospital, Fudan University, Shanghai, China Objective: To analyze the pattern of the Parkinson’s diseaserelated spatial covariance pattern (PDRP) in Chinese patients with Parkinson’s disease at various Hoehn & Yahr stages, and to assess the correlation between the PDRP expression and severity of UPDRS motor score in those patients. Methods: 18 cases of healthy control (55.6±8.7 yrs, 6 females and 12 males) and 18 cases of PD patients (57.2±9.0 yrs, 8 females and 10 males) participated in the study. Among those patients, 4 cases are at HY stage I, 5 cases II, 5 cases III, 3 cases IV, and 1 case V. The UPDRS ratings were taken 12 h off any other medications. 5 mCi 18F-FDG was intravenous injected and The PET scans were performed with an ECAT EXACT HR tomography in 3D mode. Results: The PDRP was expressed in Chinese PD patients as the same pattern as previously reported, which was characterized by lentiform, thalamic and cerebellar hypermetabolism covarying with metabolic reductions in the lateral premotor and supplementary motor area. PDRP value was 1.48±0.74 in PD group compared with −0.06±0.43 in control group. The network activity in PD patients was significantly correlated to UPDRS motor subscores Conclusion: The pattern of PDRP expressed in Chinese PD patients was consistent with previous literatures, and its value was correlated to severity of motor symptoms. It might be served as a potential biomarker for monitoring the severity of PD, which awaits confirmation from more longitudinal studies in the future. 1.5.4 BIOMARKERS FOR EARLY DIAGNOSIS OF PD P. Xu. Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China Two novel mutations of Nurr1 were found in PD patients. The Nurr1 mRNA levels of PD patients decreased by 58.6% versus controls. Early-onset PD had lower Nurr1 mRNA levels than late-onset PD. As compared to control, the expression level of Nurr1 in early-onset PD was 71.8% lower while the late-onset PD was 54.9% lower. Stratified analysis showed that all subgroups of PD (grouped according to the Hoehn and Yahr scales) had lower Nurr1 mRNA levels and the subgroup (2≤H&Y Scales <3) is the most significant one. It’s reported that Nurr1 gene could activate the transcript of several downstream genes involved in dopamine metabolism such as AAD, RXRg, Akt etc. RXR is the primary subunit receptor of Nurr1 while Akt play an important role in anti-apoptosis. The half-time period (T1/2) of Nurr1 mRNA is 12 hrs while the variant Nurr1-c is 6 hrs. Nurr1 activator SH1 could lead to a 6-fold increase of TH gene and a 2.8-fold increase of DAT gene in SH-SY5Y cells. In addition, we found that the mean serum uric acid (UA) level of PD patients was