Perampanel Inhibits α‐Synuclein Transmission in Parkinson's Disease Models

パーキンソン病モデルへのペランパネルの有効性を確認 --パーキンソン病の進行抑制治療への期待--. 京都大学プレスリリース. 2021-04-05.[Background]: The intercellular transmission of pathogenic proteins plays a key role in the clinicopathological progression of neurodegenerative diseases. Previous studies have demonstrated that this uptake and release process is regulated by neuronal activity. [Objective]: The objective of this study was to examine the effect of perampanel, an antiepileptic drug, on α‐synuclein transmission in cultured cells and mouse models of Parkinson's disease.Methods: Mouse primary hippocampal neurons were transduced with α‐synuclein preformed fibrils to examine the effect of perampanel on the development of α‐synuclein pathology and its mechanisms of action. An α‐synuclein preformed fibril‐injected mouse model was used to validate the effect of oral administration of perampanel on the α‐synuclein pathology in vivo. [Results]: Perampanel inhibited the development of α‐synuclein pathology in mouse hippocampal neurons transduced with α‐synuclein preformed fibrils. Interestingly, perampanel blocked the neuronal uptake of α‐synuclein preformed fibrils by inhibiting macropinocytosis in a neuronal activity‐dependent manner. We confirmed that oral administration of perampanel ameliorated the development of α‐synuclein pathology in wild‐type mice inoculated with α‐synuclein preformed fibrils.[Conclusion]: Modulation of neuronal activity could be a promising therapeutic target for Parkinson's disease, and perampanel could be a novel disease‐modifying drug for Parkinson's disease

Impact of Gba2 on neuronopathic Gaucher’s disease and α-synuclein accumulation in medaka (Oryzias latipes)

Homozygous mutations in the lysosomal glucocerebrosidase gene, GBA1, cause Gaucher's disease (GD), while heterozygous mutations in GBA1 are a strong risk factor for Parkinson's disease (PD), whose pathological hallmark is intraneuronal α-synuclein (asyn) aggregates. We previously reported that gba1 knockout (KO) medaka exhibited glucosylceramide accumulation and neuronopathic GD phenotypes, including short lifespan, the dopaminergic and noradrenergic neuronal cell loss, microglial activation, and swimming abnormality, with asyn accumulation in the brains. A recent study reported that deletion of GBA2, non-lysosomal glucocerebrosidase, in a non-neuronopathic GD mouse model rescued its phenotypes. In the present study, we generated gba2 KO medaka and examined the effect of Gba2 deletion on the phenotypes of gba1 KO medaka. The Gba2 deletion in gba1 KO medaka resulted in the exacerbation of glucosylceramide accumulation and no improvement in neuronopathic GD pathological changes, asyn accumulation, or swimming abnormalities. Meanwhile, though gba2 KO medaka did not show any apparent phenotypes, biochemical analysis revealed asyn accumulation in the brains. gba2 KO medaka showed a trend towards an increase in sphingolipids in the brains, which is one of the possible causes of asyn accumulation. In conclusion, this study demonstrated that the deletion of Gba2 does not rescue the pathological changes or behavioral abnormalities of gba1 KO medaka, and GBA2 represents a novel factor affecting asyn accumulation in the brains

Development of ethnographic digital collections

Περιέχει το πλήρες κείμενοΟι λαογραφικές συλλογές αποτελούν πολύτιμη πηγή μελέτης, εξερεύνησης και αξιολόγησης των εθνικών στερεοτύπων των διαφόρων διαμερισμάτων μιας χώρας, δεδομένου ότι στις συλλογές είναι καταχωρημένα ανόθευτα και πηγαία τα εγχώρια εθνοχαρακτηριστικά τους. Κατά κύριο λόγο η λαογραφία αναφέρεται στους μύθους, τα τραγούδια, τη μουσική, τα έθιμα, τη χειροτεχνία, την ενδυμασία, την αρχιτεκτονική και την προφορική παράδοση μιας κοινότητας. Η ιδιαιτερότητα και η ποικιλία ενός τομέα όπως της λαογραφίας δικαιολογεί απόλυτα την ύπαρξη συλλογών και υπο-συλλογών σύνθετης δομής και σημασιολογίας, όπως αυτές που αναφέρουμε παραπάνω. Επομένως η ανάπτυξη ψηφιακών συλλογών απαιτεί τη διατήρηση των στοιχείων που χρειάζονται για: (α) την περιγραφή του περιεχομένου της κάθε συλλογής χωριστά και (β) τη σωστή απεικόνιση της δομής των αντικειμένων στο εσωτερικό αυτής. Στόχος της εργασίας αυτής είναι η παρουσίαση μιας μεθοδολογίας για την ανάπτυξη ενός περιγραφικού μοντέλου μεταδεδομένων για λαογραφικές συλλογές. Το μοντέλο θα αποτελέσει βασικό εργαλείο για την περιγραφή του ψηφιοποιημένου λαογραφικού υλικού, την πρόσβαση σε αυτό από κατανεμημένους χρήστες και φυσικά την επικοινωνία του με άλλα συστήματα. Επιπλέον θα συμβάλλει στη διασύνδεση σύνθετων συλλογών και των αντικειμένων που περιλαμβάνουν είτε σημασιολογικά, είτε χρονικά, είτε θεματικά είτε με οποιονδήποτε άλλο τρόπο απαιτεί η φύση των συλλογών και οι ανάγκες των χρηστών

Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy.

Glial cytoplasmic inclusions (GCIs), commonly observed as α-synuclein (α-syn)-positive aggregates within oligodendrocytes, are the pathological hallmark of multiple system atrophy. The origin of α-syn in GCIs is uncertain; there is little evidence of endogenousα-syn expression in oligodendrocyte lineage cells, oligodendrocyte precursor cells (OPCs),and mature oligodendrocytes (OLGs). Here, based on in vitro analysis using primary rat cell cultures, we elucidated that preformed fibrils (PFFs) generated from recombinant human α-syn trigger multimerization and an upsurge of endogenous α-syn in OPCs, which is attributable to insufficient autophagic proteolysis. RNA-seq analysis of OPCs revealed that α-syn PFFs interfered with the expression of proteins associated with neuromodulation and myelination. Furthermore, we detected cytoplasmic α-syn inclusions in OLGs through differentiation of OPCs pre-incubated with PFFs. Overall, our findings suggest the possibility of endogenous α-syn accumulation in OPCs that contributes to GCI formation and perturbation of neuronal/glial support in multiple system atrophy brains

生存可能な神経型ゴーシェ病モデルメダカは軸索にアルファシヌクレイン蓄積を示す

京都大学0048新制・課程博士博士(医学)甲第19178号医博第4020号新制||医||1010(附属図書館)32170京都大学大学院医学研究科医学専攻(主査)教授 髙橋 淳, 教授 渡邉 大, 教授 村井 俊哉学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Inoculation of α-synuclein preformed fibrils into the mouse gastrointestinal tract induces Lewy body-like aggregates in the brainstem via the vagus nerve

Abstract: Background Intraneuronal α-synuclein (α-Syn) aggregates known as Lewy bodies (LBs) and the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) are the pathological hallmarks of Parkinson’s disease (PD). Braak’s hypothesis based on autopsy studies suggests that Lewy pathology initially occurs in the enteric nervous system (ENS) and then travels retrogradely to the dorsal motor nucleus of the vagus nerve (dmX), proceeding from there in a caudo-rostral direction. Recent evidence that α-Syn aggregates propagate between interconnected neurons supports this hypothesis. However, there is no direct evidence demonstrating this transmission from the ENS to the dmX and then to the SNpc. Methods We inoculated α-Syn preformed fibrils (PFFs) or phosphate-buffered saline (PBS) into the mouse gastric wall and analyzed the progression of the pathology. Results The mice inoculated with α-Syn PFFs, but not with PBS, developed phosphorylated α-Syn (p-α-Syn)–positive LB-like aggregates in the dmX at 45 days postinoculation. This aggregate formation was completely abolished when vagotomy was performed prior to inoculation of α-Syn PFFs, suggesting that the aggregates in the dmX were retrogradely induced via the vagus nerve. Unexpectedly, the number of neurons containing p-α-Syn–positive aggregates in the dmX decreased over time, and no further caudo-rostral propagation beyond the dmX was observed up to 12 months postinoculation. P-α-Syn–positive aggregates were also present in the myenteric plexus at 12 months postinoculation. However, unlike in patients with PD, there was no cell-type specificity in neurons containing those aggregates in this model. Conclusions: These results indicate that α-Syn PFF inoculation into the mouse gastrointestinal tract can induce α-Syn pathology resembling that of very early PD, but other factors are apparently required if further progression of PD pathology is to be replicated in this animal model