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

パーキンソン病の前駆期モデルにおいて、GBAのハプロ不全は脂質代謝変化を通してアルファシヌクレイン病理を加速させる

京都大学0048新制・課程博士博士(医学)甲第22001号医博第4515号新制||医||1038(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 井上 治久, 教授 林 康紀, 教授 高橋 淳学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Animal Model for Prodromal Parkinson’s Disease

Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and subsequent motor symptoms, but various non-motor symptoms (NMS) often precede motor symptoms. Recently, NMS have attracted much attention as a clue for identifying patients in a prodromal stage of PD, which is an excellent point at which to administer disease-modifying therapies (DMTs). These prodromal symptoms include olfactory loss, constipation, and sleep disorders, especially rapid eye movement sleep behavior disorder (RBD), all of which are also important for elucidating the mechanisms of the initiation and progression of the disease. For the development of DMTs, an animal model that reproduces the prodromal stage of PD is also needed. There have been various mammalian models reported, including toxin-based, genetic, and alpha synuclein propagation models. In this article, we review the animal models that exhibit NMS as prodromal symptoms and also discuss an appropriate prodromal model and its importance for the development of DMT of PD

Ca²⁺–Calmodulin–Calcineurin Signaling Modulates α‐Synuclein Transmission

BACKGROUND: The intercellular transmission of pathogenic proteins plays a crucial role in the progression of neurodegenerative diseases. Previous research has shown that the neuronal uptake of such proteins is activity-dependent; however, the detailed mechanisms underlying activity-dependent α-synuclein transmission in Parkinson's disease remain unclear. OBJECTIVE: To examine whether α-synuclein transmission is affected by Ca²⁺ -calmodulin-calcineurin signaling in cultured cells and mouse models of Parkinson's disease. METHODS: Mouse primary hippocampal neurons were used to examine the effects of the modulation of Ca²⁺ -calmodulin-calcineurin signaling on the neuronal uptake of α-synuclein preformed fibrils. The effects of modulating Ca²⁺ -calmodulin-calcineurin signaling on the development of α-synuclein pathology were examined using a mouse model injected with α-synuclein preformed fibrils. RESULTS: Modulation of Ca²⁺ -calmodulin-calcineurin signaling by inhibiting voltage-gated Ca²⁺ channels, calmodulin, and calcineurin blocked the neuronal uptake of α-synuclein preformed fibrils via macropinocytosis. Different subtypes of voltage-gated Ca²⁺ channel differentially contributed to the neuronal uptake of α-synuclein preformed fibrils. In wild-type mice inoculated with α-synuclein preformed fibrils, we found that inhibiting calcineurin ameliorated the development of α-synuclein pathology. CONCLUSION: Our data suggest that Ca²⁺ -calmodulin-calcineurin signaling modulates α-synuclein transmission and has potential as a therapeutic target for Parkinson's disease. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Striatal-Inoculation of α-Synuclein Preformed Fibrils Aggravated the Phenotypes of REM Sleep without Atonia in A53T BAC-SNCA Transgenic Mice

Accumulation of α-synuclein (α-syn) is the pathological hallmark of α-synucleinopathy. Rapid eye movement (REM) sleep behavior disorder (RBD) is a pivotal manifestation of α-synucleinopathy including Parkinson’s disease (PD). RBD is clinically confirmed by REM sleep without atonia (RWA) in polysomnography. To accurately characterize RWA preceding RBD and their underlying α-syn pathology, we inoculated α-syn preformed fibrils (PFFs) into the striatum of A53T human α-syn BAC transgenic (A53T BAC-SNCA Tg) mice which exhibit RBD-like phenotypes with RWA. RWA phenotypes were aggravated by PFFs-inoculation in A53T BAC-SNCA Tg mice at 1 month after inoculation, in which prominent α-syn pathology in the pedunculopontine nucleus (PPN) was observed. The intensity of RWA phenotype could be dependent on the severity of the underlying α-syn pathology

Lewy Body Disease Primate Model with α‐Synuclein Propagation from the Olfactory Bulb

パーキンソン病の認知機能障害は鼻からはじまる？ --レヴィ小体病における嗅覚系伝播経路の解明--. 京都大学プレスリリース. 2022-08-23.[Background] Lewy body diseases (LBDs), which are pathologically defined as the presence of intraneuronal α-synuclein (α-Syn) inclusions called Lewy bodies, encompass Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies. Autopsy studies have shown that the olfactory bulb (OB) is one of the regions where Lewy pathology develops and initiates its spread in the brain. [Objective] This study aims to clarify how Lewy pathology spreads from the OB and affects brain functions using nonhuman primates. [Methods] We inoculated α-Syn preformed fibrils into the unilateral OBs of common marmosets (Callithrix jacchus) and performed pathological analyses, manganese-enhanced magnetic resonance imaging, and 18F-fluoro-2-deoxy-d-glucose positron emission tomography up to 6 months postinoculation. [Results] Severe α-Syn pathology was observed within the olfactory pathway and limbic system, while mild α-Syn pathology was seen in a wide range of brain regions, including the substantia nigra pars compacta, locus coeruleus, and even dorsal motor nucleus of the vagus nerve. The brain imaging analyses showed reduction in volume of the OB and progressive glucose hypometabolism in widespread brain regions, including the occipital lobe, and extended beyond the pathologically affected regions. [Conclusions] We generated a novel nonhuman primate LBD model with α-Syn propagation from the OB. This model suggests that α-Syn propagation from the OB is related to OB atrophy and cerebral glucose hypometabolism in LBDs

Ca²⁺–Calmodulin–Calcineurin Signaling Modulates α‐Synuclein Transmission

BACKGROUND: The intercellular transmission of pathogenic proteins plays a crucial role in the progression of neurodegenerative diseases. Previous research has shown that the neuronal uptake of such proteins is activity-dependent; however, the detailed mechanisms underlying activity-dependent α-synuclein transmission in Parkinson's disease remain unclear. OBJECTIVE: To examine whether α-synuclein transmission is affected by Ca²⁺ -calmodulin-calcineurin signaling in cultured cells and mouse models of Parkinson's disease. METHODS: Mouse primary hippocampal neurons were used to examine the effects of the modulation of Ca²⁺ -calmodulin-calcineurin signaling on the neuronal uptake of α-synuclein preformed fibrils. The effects of modulating Ca²⁺ -calmodulin-calcineurin signaling on the development of α-synuclein pathology were examined using a mouse model injected with α-synuclein preformed fibrils. RESULTS: Modulation of Ca²⁺ -calmodulin-calcineurin signaling by inhibiting voltage-gated Ca²⁺ channels, calmodulin, and calcineurin blocked the neuronal uptake of α-synuclein preformed fibrils via macropinocytosis. Different subtypes of voltage-gated Ca²⁺ channel differentially contributed to the neuronal uptake of α-synuclein preformed fibrils. In wild-type mice inoculated with α-synuclein preformed fibrils, we found that inhibiting calcineurin ameliorated the development of α-synuclein pathology. CONCLUSION: Our data suggest that Ca²⁺ -calmodulin-calcineurin signaling modulates α-synuclein transmission and has potential as a therapeutic target for Parkinson's disease. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society