Prion-like spreading of pathological α-synuclein in brain.

Abstract

α-Synuclein is the major component of filamentous inclusions that constitute the defining characteristic of neurodegenerative α-synucleinopathies. However, the molecular mechanisms underlying α-synuclein accumulation and spread are unclear. Here we show that intracerebral injections of sarkosyl-insoluble α-synuclein from brains of patients with dementia with Lewy bodies induced hyperphosphorylated α-synuclein pathology in wild-type mice. Furthermore, injection of fibrils of recombinant human and mouse α-synuclein efficiently induced similar α-synuclein pathologies in wild-type mice. C57BL/6J mice injected with α-synuclein fibrils developed abundant Lewy body/Lewy neurite-like pathology, whereas mice injected with soluble α-synuclein did not. Immunoblot analysis demonstrated that endogenous mouse α-synuclein started to accumulate 3 months after inoculation, while injected human α-synuclein fibrils disappeared in about a week. These results indicate that α-synuclein fibrils have prion-like properties and inoculation into wild-type brain induces α-synuclein pathology in vivo. This is a new mouse model of sporadic α-synucleinopathy and should be useful for elucidating progression mechanisms and evaluating disease-modifying therapy.

• Authors: Masami Masuda-Suzukake, Takashi Nonaka, Masato Hosokawa, Takayuki Oikawa, Tetsuaki Arai, Haruhiko Akiyama, David M A Mann, Masato Hasegawa
• Journal: Brain : a journal of neurology (Brain) Vol. 136 Issue Pt 4 Pg. 1128-38 (Apr 2013) ISSN: 1460-2156 [Electronic] England
• PMID: 23466394 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Prions
• Recombinant Proteins
• SNCA protein, human
• Snca protein, mouse
• alpha-Synuclein

Topics

• Administration, Intranasal
• Animals
• Behavior, Animal (physiology)
• Brain (metabolism, pathology, physiopathology)
• Disease Models, Animal
• Female
• Humans
• Injections, Intraventricular
• Lewy Body Disease (metabolism, pathology, physiopathology)
• Mice
• Mice, Inbred C57BL
• Prions (metabolism)
• Recombinant Proteins (administration & dosage, toxicity)
• Time Factors
• alpha-Synuclein (administration & dosage, metabolism, toxicity)