title: Alpha-synuclein-positive structures induced in leupeptin-infused rats.
abstract: Abnormal accumulation of alpha-synuclein is regarded as a key pathological step in a wide range of neurodegenerative processes, not only in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) but also in multiple-system atrophy (MSA). Nevertheless, the mechanism of alpha-synuclein accumulation remains unclear. Leupeptin, a protease inhibitor, has been known to cause various neuropathological changes in vivo resembling those of aging or neurodegenerative processes in the human brain, including the accumulation of neuronal processes and neuronal cytoskeletal abnormalities leading to neurofibrillary tangle (NFT)-like formations. In the present study, we administered leupeptin into the rat ventricle and found that alpha-synuclein-positive structures appeared widely in the neuronal tissue, mainly in neuronal processes of the fimbria and alveus. Immunoelectron microscopic study revealed that alpha-synuclein immunoreactivity was located in the swollen axons of the fimbria and alveus, especially in the dilated presynaptic terminals. In addition colocalization of alpha-synuclein with ubiquitin was rarely observed in confocal laser-scan image. This is the first report of experimentally induced in vivo accumulation of alpha-synuclein in non-transgenic rodent brain injected with a well-characterized protease inhibitor by an infusion pump. The present finding suggests that the local accumulation of alpha-synuclein might be induced by the impaired metabolism of alpha-synuclein, which are likely related to lysosomal or ubiquitin-independent proteasomal systems.
authors.affiliation: Department of Neuropsychiatry, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan. taka528i@kcc.zaq.ne.jp
authors.forename: T
authors.initials: T
authors.lastname: Nakajima
authors.forename: S
authors.initials: S
authors.lastname: Takauchi
authors.forename: K
authors.initials: K
authors.lastname: Ohara
authors.forename: M
authors.initials: M
authors.lastname: Kokai
authors.forename: R
authors.initials: R
authors.lastname: Nishii
authors.forename: S
authors.initials: S
authors.lastname: Maeda
authors.forename: A
authors.initials: A
authors.lastname: Takanaga
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.forename: M
authors.initials: M
authors.lastname: Takeda
authors.forename: M
authors.initials: M
authors.lastname: Seki
authors.forename: Y
authors.initials: Y
authors.lastname: Morita
mesh_terms: D000818:Animals; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage; D020712:Fornix, Brain / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D015918:Infusion Pumps, Implantable; D007276:Injections, Intraventricular; D007976:Leupeptins / Q000008:administration & dosage*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D022142:Secretory Vesicles / Q000187:drug effects / Q000648:ultrastructure; D051843:Synucleins; D051844:alpha-Synuclein
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009419:Nerve Tissue Proteins; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein; C032854:leupeptin