Neuroinflammation in Parkinson's Disease and Related Disorders: A Lesson from Genetically Manipulated Mouse Models of α-Synucleinopathies

Neuroinflammation in Parkinson's disease (PD) is a chronic process that is associated with alteration of glial cells, including astrocytes and microglia. However, the precise mechanisms remain obscure. To better understand neuroinflammation in PD, we focused on glial activation in α-synuclein (αS) transgenic and related model mice. In the majority of αS transgenic mice, astrogliosis was observed concomitantly with accumulation of αS during the early stage of neurodegeneration. However, microglia were not extensively activated unless the mice were treated with lipopolysaccharides or through further genetic modification of other molecules, including familial PD risk factors. Thus, the results in αS transgenic mice and related model mice are consistent with the idea that neuroinflammation in PD is a double-edged sword that is protective in the early stage of neurodegeneration but becomes detrimental with disease progression

Distinct mechanisms of axonal globule formation in mice expressing human wild type α-synuclein or dementia with Lewy bodies-linked P123H ß-synuclein

BACKGROUND: Axonopathy is critical in the early pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Axonal swellings such as globules and spheroids are a distinct feature of axonopathy and our recent study showed that transgenic (tg) mice expressing DLB-linked P123H β-synuclein (P123H βS) were characterized by P123H βS-immunoreactive axonal swellings (P123H βS-globules). Therefore, the objectives of this study were to evaluate α-synuclein (αS)-immunoreactive axonal swellings (αS-globules) in the brains of tg mice expressing human wild-type αS and to compare them with the globules in P123H βS tg mice. RESULTS: In αS tg mice, αS-globules were formed in an age-dependent manner in various brain regions, including the thalamus and basal ganglia. These globules were composed of autophagosome-like membranous structures and were reminiscent of P123H βS-globules in P123H βS tg mice. In the αS-globules, frequent clustering and deformation of mitochondria were observed. These changes were associated with oxidative stress, based on staining of nitrated αS and 4-hydroxy-2-nonenal (4-HNE). In accord with the absence of mitochondria in the P123H βS-globules, staining of nitrated αS and 4-HNE in these globules was weaker than that for αS-globules. Leucine-rich repeat kinase 2 (LRRK2), the PARK8 of familial PD, was detected exclusively in αS-globules, suggesting a specific role of this molecule in these globules. CONCLUSIONS: Lysosomal pathology was similarly observed for both αS- and P123H βS-globules, while oxidative stress was associated with the αS-globules, and to a lesser extent with the P123H βS-globules. Other pathologies, such as mitochondrial alteration and LRRK2 accumulation, were exclusively detected for αS-globules. Collectively, both αS- and P123H βS-globules were formed through similar but distinct pathogenic mechanisms. Our findings suggest that synuclein family members might contribute to diverse axonal pathologies

α-Synuclein and DJ-1 as Potential Biological Fluid Biomarkers for Parkinson’s Disease

Parkinson’s disease (PD) is the most common form of movement disorder and affects approximately 4% of the population aged over 80 years old. Currently, PD cannot be prevented or cured, and no single diagnostic biomarkers are available. Notably, recent studies suggest that two familial PD-linked molecules, α-synuclein and DJ-1, are present in cerebrospinal fluid (CSF) and that their levels may be altered during the progression of PD. In this regard, sensitive and accurate methods for evaluation of α-synuclein and DJ-1 levels in the CSF and blood have been developed, and the results suggest that the levels of both molecules are significantly decreased in the CSF in patients with PD compared with age-matched controls. Furthermore, specific detection and quantification of neurotoxic oligometric forms of α-synuclein in the blood using enzyme-linked immunosorbent assays might be expected as potential peripheral biomarkers for PD, although further validation is required. Currently, neither α-synuclein nor DJ-1 is satisfactory as a single biomarker for PD, but combinatory evaluation of these biological fluid molecules with other biomarkers and imaging techniques may provide reliable information for diagnosis of PD

Kansai University Library 100th anniversary

目次 【序文】記念誌の刊行にあたって（図書館長　内田慶市）図書館創設100周年によせて（学長　楠見晴重）記念誌の編集について【第1部　この20年を振り返って】高槻図書室開館（広瀬雅子）…3阪神・淡路大震災（高橋真澄）…8図書館システムの変遷（徳岡久実・濱生快彦）…12図書館ビジョン7項目の制定（濱生快彦）…20図書館におけるアウトソーシング（高橋真澄）…26電子展示（濱生快彦）…36市民利用開始（広瀬雅子）…41図書館ウェブサイト（濱生快彦）…442010プロジェクトによる新図書館（高橋真澄・田中恵美）…48図書館リニューアル工事（新谷大二郎）…60図書館の現在と未来（堀口和弘）…68【第2部　図書館に想う】関西大学図書館創設100周年に寄せて（市川訓敏）…79図書館の思い出、図書館への思い（北川勝彦）…85図書館在職時の思い出（柴田真一）…91数々の貴重書（田中登）…95関西大学図書館100周年にあたって : 私の夢想する図書館（内田慶市）…100【第3部　図書館の文庫・コレクション】文庫・コレクションの紹介（鵜飼香織）…111【第4部　資料編】図書館年譜（明治19.3 ～平成26.7）…119サービスに係る統計（総合図書館）…146サービスに係る統計（高槻図書室・ミューズ大学図書館・堺キャンパス図書館）…148蔵書数の推移…149図書費執行額の推移…150展示一覧…152他大学図書館との協定一覧…160【「図書館コラム」】新人時代の思い出（高松和美）…11エレベーターにまつわる話（吉田有輝）…19泣き別れたり、親子になったり（嶋田有理香）…35貴重なのは本だけ？貴重書担当のつぶやき（大上良樹）…40会長校のころ（金東瀅）…46『コアラ博士』にまつわるあれこれ（松本和剛）…57広報誌『KULione 』誕生秘話（白髪友賀）…59本と夢を運んだテレリフト（芝谷秀司）…66LOUIS VUITTON（加藤博之）…7

Role of α- and β-Synucleins in the Axonal Pathology of Parkinson’s Disease and Related Synucleinopathies

Axonal swellings are histological hallmarks of axonopathies in various types of disorders in the central nervous system, including neurodegenerative diseases. Given the pivotal role of axonopathies during the early phase of neurodegenerative process, axonal swellings may be good models which may provide some clues for early pathogenesis of α-synucleinopathies, including Parkinson’s disease and dementia with Lewy bodies (DLB). In this mini-review, such a possibility is discussed based on our recent studies as well as other accumulating studies. Consistent with the current view that dysfunction in the autophagy-lysosomal system may play a major role in the formation of axonal swellings, our studies showed globule, small axonal swellings, derived from transgenic mice expressing either human wild-type α-synuclein (αS-globule) or DLB-linked P123H β-synuclein (βS-globule), contained autophagosome-like membranes. However, other pathological features, such as abnormal mitochondria, enhanced oxidative stress and LRRK2 accumulation, were observed in the αS-globules, but not in the βS-globules. Collectively, it is predicted that αS and βS may be involved in axonopathies through similar but distinct mechanisms, and thus, contribute to diverse axonal pathologies. Further studies of the axonal swellings may lead to elucidating the pathogenic mechanism of early α-synucleinopathies and illuminating a strategy for a disease-modifying therapy against these devastating disorders

The impact of normal serum complement levels on the disease classification and clinical characteristics in systemic lupus erythematosus

Abstract Background Some patients have normal levels of complement during the diagnosis of systemic lupus erythematosus (SLE), although decreased serum levels of complement are a hallmark of the active phase of the disease. This study investigated the clinical characteristics, impact on the classification of SLE, and the prognosis of patients with SLE who had normal serum complement levels at initial diagnosis (N-com). Methods We evaluated 21 patients with N-com and 96 patients with hypocomplementemia at the initial diagnosis of SLE (H-com). The classification rates among the American College of Rheumatology (ACR) 1997, Systemic Lupus International Collaborating Clinics (SLICC) 2012, European League Against Rheumatism (EULAR)/ACR 2019 criteria, and clinical and immunological involvements were compared between SLE patients with N-com and H-com. Relapse and organ damage based on the SLICC/ACR damage index were also evaluated. Results The classification rates of SLE were not significantly different in the ACR, SLICC, and EULAR/ACR criteria between the N-com and H-com groups. Patients with N-com had no significant differences in the classification rates among the three criteria, whereas patients with H-com had lower classification rates in the ACR criteria than in the SLICC criteria. A lower incidence of renal manifestation, less positivity for anti-dsDNA antibody, and a higher incidence of fever were observed in patients with N-com than in those with H-com. The occurrence of relapse and organ damage was not significantly different between patients with N-com and H-com. Conclusion Patients with N-com were less involved in renal manifestation and anti-dsDNA antibody positivity but had a higher incidence of fever than those with H-com, while having no disadvantage in SLE classification processes. Serum complement levels at the initial diagnosis of SLE may not predict prognosis