analysis of abnormal neuronal excitability mediated by alpha-synuclein oligomer

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591265
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Department of Clinical Research, National Hospital Organization Utano National Hospital
• Principal Investigator: KENJI Yamamoto 独立行政法人国立病院機構(宇多野病院臨床研究部), その他部局等, 研究員 (50378775)
• Co-Investigator(Kenkyū-buntansha): SAWADA Hideyuki 独立行政法人国立病院機構, 宇多野病院臨床研究部, 臨床研究部長 (30335260) ; YAMAKAWA Kentaro 独立行政法人国立病院機構, 宇多野病院臨床研究部, 研究員 (70447960)
• Project Period (FY): 2011 – 2013
• Keywords: αシヌクレイン / オリゴマー / パーキンソン病 / レビー小体型認知症 / カリウムチャンネル / カルシウム / 膜興奮性 / パッチクランプ

Research Abstract

We examined the action of alpha-synuclein oligomers on neuronal excitabilities by injecting protein into pyramidal neurons in mouse cortical slices through whole-cell patch pipettes.
Western blot analysis showed that the pipette solution including alpha-synuclein incubated with dopamine (aS+DA), had higher order oligomer. Intracellular application of aS+DA suppressed spike firing during current injection. Nimodipine and apamin blocked the effect of aS+DA on spike firing. aS+DA prolonged the duration of spike afterhyperpolarization (AHP) and increased the charge transfer carried by the current during AHP under current clamp, both of which were inhibited by apamin.
These results suggest that alpha-synuclein oligomers suppress spike frequency by enhancing AHP, and apamin-sensitive SK-type calcium-activated potassium channel is involved with the enhancement. This mechanism may cause the downregulation of neocortical activities in Parkinson's disease and dementia with Lewy bodies.

Research Products

• [Journal Article] Subclinical Elevation of Plasma C-Reactive Protein and Illusions/Hallucinations in Subjects with Parkinson's Disease : Case–control Study (2014)
  • Author(s): Sawada H, Oeda T, Umemura A, Tomita S, Hayashi R, Kohsaka M, Yamamoto K, Sudoh S, Sugiyama H
  • Journal Title: PLoS One Volume: 9 Pages: e85886
  • DOI: 10.1371/journal.pone.0085886
  • Peer Reviewed
• [Journal Article] Catecholamines and Neurodegeneration in Parkinson's Disease—From Diagnostic Marker to Aggregations ofα-Synuclein (2013)
  • Author(s): Sawada H, Oeda T, Yamamoto K
  • Journal Title: Diagnostics Volume: 3(2) Pages: 210-221
  • DOI: 10.3390/diagnostics3020210
  • Peer Reviewed
• [Journal Article] Trigger medications and patient-related risk factors for Parkinson disease psychosis requiring anti-psychotic drugs : a retrospective cohort study (2013)
  • Author(s): Sawada H, Oeda T, Yamamoto K, Umemura A, Tomita S, Hayashi R, Kohsaka M, Kawamura T
  • Journal Title: BMC Neurol Volume: 13 Pages: 145
  • DOI: 10.1186/1471-2377-13-145
  • Peer Reviewed
• [Journal Article] Diagnostic accuracy of apparent diffusion coefficient and 123I-metaiodobenzyl -guanidine for differentiation of multiple system atrophy and Parkinson's disease (2013)
  • Author(s): Umemura A, Oeda T, Hayashi R, Tomita S, Kohsaka M, Yamamoto K, Sawada H
  • Journal Title: PLoS One Volume: 8 Pages: e61066
  • DOI: 10.1371/journal.pone.0061066
  • Peer Reviewed
• [Journal Article] Suppression of a neocortical potassium channel activity by intra- cellular amyloid-βand its rescue with Homerla (2011)
  • Author(s): Yamamoto K, Ueta Y, Wang L, Yamamoto R, Inoue N, Inokuchi K, Aiba A, Yonekura H, Kato N
  • Journal Title: J Neurosci Volume: 31(31) Pages: 11100-11109
  • DOI: 10.1523/JNEUROSCI.6752-10.2011
  • Peer Reviewed
• [Presentation] Down-regulation of spike frequency by alpha-synuclein oligomer (2014)
  • Author(s): 山本兼司、山川健太郎、澤田秀幸
  • Organizer: 第55日本神経学会学術大会
  • Place of Presentation: 福岡
  • Year and Date: 2014-05-22
• [Presentation] Suppression of spike frequency byα-Synuclein oligomer in neocortical pyramidal neurons (2013)
  • Author(s): K. Yamamoto, K. Yamakawa, H. Sawada
  • Organizer: 21^<th> World Congress of Neurology
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2013-09-24
• [Presentation] αシヌクレインオリゴマーによる大脳皮質錐体細胞の発火制御機構 (2013)
  • Author(s): 山本兼司、山川健太郎、澤田秀幸
  • Organizer: 第36回日本神経科学大会
  • Place of Presentation: 京都
  • Year and Date: 2013-06-20
• [Presentation] αシヌクレインオリゴマーは大脳皮質錐体細胞の発火頻度を低下させる (2013)
  • Author(s): 山本兼司、山川健太郎、澤田秀幸
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2013-05-29
• [Presentation] Levodopa responsiveness for progressive supranuclear palsy can predict early onset of aspiration pneumonia (2012)
  • Author(s): Tomita S, Oeda T, Nakano H, Umemura A, Hayashi R, Yamamoto K, Sawada H
  • Organizer: 16^<th> Congress of the European Federation of Neurological Societies
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2012-09-10
• [Presentation] Nutritional status as a predictor of the mortality in patients with Parkinson's disease (2012)
  • Author(s): Motoyama R, Oeda T, Hari Y, Hayashi R, Uemura A, Tomita S, Kohsaka M, Yamamoto K, Konishi T, Sawada H
  • Organizer: 16^<th> Congress of the European Federation of Neurological Societies
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2012-09-09
• [Presentation] Brain MRI apparent diffusion co-efficient (ADC) in Parkinson's disease with dementia (2012)
  • Author(s): Umemura A, Oeda T, Kohsaka M,Tomita S, Hayashi R, Yamamoto K, Sawada H
  • Organizer: 16^<th> Congress of the European Federation of Neurological Societies
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2012-09-09
• [Presentation] Ocular application of oxybuprocaine hydrochloride against apraxia of lid opening : a randomized controlled trial (2012)
  • Author(s): Kohsaka M, Oeda T, Nakano H, Umemura A, Tomita S, Hayashi R, Yamamoto K, Sawada H
  • Organizer: 16^<th> Congress of the European Federation of Neurological Societies
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2012-09-09
• [Presentation] Hallucinations and Delusions in Patients with Parkinson's Disease - Evaluation by the Parkinson Psychosis Questionnaire (2011)
  • Author(s): Sawada H, Oeda T, Umemura A, Tomita S, Hayashi R, Kohsaka M, Nakano H, Yamamoto K
  • Organizer: 15^<th> Congress of the European Federation of Neurological Societies
  • Place of Presentation: Budapest, Hungary
  • Year and Date: 2011-09-12
• [Presentation] Role of Brain MRI Apparent Diffusion Coefficient (ADC) in the Differential Diagnosis of Parkinson's Disease (PD) and Progressive Supranuclear Palsy (PSP) (2011)
  • Author(s): Umemura A, Oeda T, Kohsaka M,Tomita S, Hayashi R, Yamamoto K, Sawada H
  • Organizer: 15^<th> Congress of the European Federation of Neurological Societies
  • Place of Presentation: Budapest, Hungary
  • Year and Date: 2011-09-12