公募シンポジウム

公募シンポジウムレビー小体病の新たな創薬標的の探索と治療開発・予測技術の新展開

7月7日（金）　8:30-10:30　Room C 2SY①-1 Novel interactions with lipids that promote alpha-synuclein aggregation and regulate structural polymorphism 角田　渓太, 池中　建介, Chi-Jing Choong, Cesar Aguirre 大阪大学　神経内科 Keita Kakuda, Kensuke Ikenaka, Chi-Jing Choong, Cesar Aguirre Dept. of Neurology. Osaka Univ., Osaka, Japan Misfolded α-synuclein (αSyn) aggregation, a main component of Lewy body, is a pathological hallmark of Parkinson’s disease (PD). Previously we have shown that the lipid content exists at the center of the Lewy bodies. Several risk genes for PD, including GBA1, are known to be involved in lipid metabolism. In our recent work, we found that loss of function of synaptojanin 1 (SYJN1), the gene responsible for a familial PD (PARK20) and involved in the dephosphorylation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), has a profound link to αSyn pathology. Analysis of SYNJ1 knockout cells and SYNJ1 mutant C.elegans models showed that SYNJ1 dysfunction promotes the accumulation of αSyn aggregation. Furthermore, immunohistochemical analysis of postmortem brains from sporadic PD patients showed upregulation of PIP3 which co-localized with αSyn. Further in-vitro experiments revealed the strongest interaction between PIP3 and αSyn, and that PIP3 promotes fibrillation ofαSyn, which has similar structural and biochemical characteristics to fibrils from PD brains. The link between structural polymorphisms of αSyn fibrils and disease diversity in synucleinopathies is an important theme of our research, and this session will also address lysosomal membrane toxicity due to structural polymorphism related to susceptibility to propagation.		7月7日（金）　8:30-10:30　Room C 2SY①-2 レビー小体病における脂肪酸結合タンパク質の生理機能解明と新規創薬戦略 Impact of fatty-acid binding protein in Lewy body diseases and its potential for novel therapeutic target 川畑　伊知郎¹, 武田　篤², 福永　浩司^1,3 1. 東北大・薬・先進脳, 2. 国立仙台西多賀病院・脳神経内科, 3. BRIファーマ(株) Ichiro Kawahata¹, Atsuhi Takeda², Kohji Fukunaga^1,3 1. Grad Sch Pharm Sci., Tohoku Univ., Sendai, Japan, 2. NHO Sendai Nishitaga Hosp., Sendai, Japan, 3. BRI Pharma Inc., Sendai, Japan Fatty acid-binding proteins (FABPs) are soluble proteins with a molecular weight of approximately 15 kDa that are involved in the intracellular transport of fatty acids. FABP type 3 (FABP3) is essential for the intracellular uptake, aggregation, and brain propagation of α-synuclein, the protein responsible for Lewy body disease. In this symposium, we aimed to introduce the physiological significance of FABP3 in the pathogenesis of Lewy body disease and discover novel potential drugs targeting FABP3-α-synuclein interaction, elucidating the therapeutic effects. We prepared the FABP3 ligand, a small molecule targeting FABP3, which suppressed intracellular uptake and propagation of α-synuclein, improving cognitive and motor dysfunction in Lewy body disease-model mice. Further, a novel decoy peptide targeting the C-terminus of α-synuclein showed similar therapeutic effects, inhibiting α-synuclein phosphorylation. These data demonstrated that FABP3 is associated with the pathogenesis of Lewy body diseases and is a novel potential therapeutic target. We are currently conducting preclinical studies, which accelerate extending healthy brain life expectancy in the super-aging society.

7月7日（金）　8:30-10:30　Room C 2SY①-3 Search for novel surrogate markers in patients with Lewy body disease 武田　篤国立病院機構仙台西多賀病院 Atsushi Takeda National Hospital Organization Sendai Nishitaga Hospital We performed skin histology on patients with Parkinson's disease and related disorders and found that α-synuclein aggregates were present in macrophages as well as peripheral nerve endings in the skin of more than 80% of Parkinson's disease patients. Although various lipid abnormalities have been reported to be associated with neurodegenerative diseases, it is still unclear whether lipid abnormalities play important roles in neurodegenerative diseases. To investigate which lipid abnormalities are most involved in neurodegenerative diseases, we performed lipid analysis using blood lipidomics in patients with neurodegenerative diseases (Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Alzheimer's disease, progressive supranuclear palsy) and healthy control subjects. The results showed that blood sphingosine-1-phosphate (S1P) was significantly lower in all neurodegenerative disease groups than in healthy controls, and blood monohexylceramide (MonCer) and blood lactosylceramide (LacCer) were significantly higher in all neurodegenerative disease groups than in healthy controls. These results suggest that skin histology can be an important test for the definitive diagnosis of Parkinson's disease and that blood sphingolipid abnormalities may be a new diagnostic biomarker common to neurodegenerative diseases.		7月7日（金）　8:30-10:30　Room C 2SY①-4 レビー小体型認知症の早期予測技術と鑑別法の開発 Development of plasma biomarkers to discriminate the prodromal dementia with Lewy body 福永　浩司^1,2, 関森　智紀², 大泉　英樹³, 武田　篤³, 川畑　伊知郎² 1. BRI ファーマ株式会社, 2. 東北大学大学院　薬学研究科　薬理学分野, 3. 国立病院機構　仙台西多賀病院 Kohji Fukunaga^1,2, Tomoki Sekimori², Hideki Oizumi³, Atsushi Takeda³, Ichiro Kawahata² 1. BRI Pharma Inc., 2. Department of Pharmacology, Graduate School of Pharmaceutical Science, Tohoku University, 3. Department of Neurology, National Hospital Organization Sendai Nishitaga Hospital, Sendai The core clinical features of dementia with Lewy body (DLB) are fluctuating cognition, recurrent visual hallucinations, REM sleep behavior disorder, and Parkinsonism. DLB patients have comorbid Alzheimer’s disease (AD) pathology, so the discrimination is hard from AD in the early stage. After symptom onset, the indicative biomarkers are used to measure dopamine uptake in the basal ganglia on positron emission tomography (PET) or single-photon emission computed tomography (SPECT). Although the plasma levels of Aβ42/40, phosphorylated tau (p-tau181), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) are useful as biomarkers for Alzheimer disease and DLB, the surrogate and discriminating biomarkers to discriminate the prodromal AD and DLB are not available. We recently introduced the attractive biomarkers to discriminate the mild cognitive impairment (MCI) patients from AD and DLB patients. Fatty acid binding proteins (FABPs) such as FABP3, FABP5 and FABP7 are also indicative neuroinflammation biomarkers associated with neurodegenerative disorders. In this symposium, we report the plasma levels of FABP3, FABP5 and FABP7 measured using single molecule array (Simoa) and discuss the possibilities as prodromal biomarkers to discriminate between AD and DLB.