Complement and Coagulation Cascades are Potentially Involved in Dopaminergic Neurodegeneration in α-Synuclein-Based Mouse Models of Parkinson's Disease

Shi Xun Ma, Bo Am Seo, Donghoon Kim, Yulan Xiong, Seung Hwan Kwon, Saurav Brahmachari, Sangjune Kim, Tae In Kam, Raja Sekhar Nirujogi, Sang Ho Kwon, Valina L. Dawson, Ted M. Dawson, Akhilesh Pandey, Chan Hyun Na, Han Seok Ko

Research output: Contribution to journalArticlepeer-review

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder that results in motor dysfunction and, eventually, cognitive impairment. α-Synuclein protein is known as a central protein to the pathophysiology of PD, but the underlying pathological mechanism still remains to be elucidated. In an effort to understand how α-synuclein underlies the pathology of PD, various PD mouse models with α-synuclein overexpression have been developed. However, systemic analysis of the brain proteome of those mouse models is lacking. In this study, we established two mouse models of PD by injecting α-synuclein preformed fibrils (PFF) or by inducing overexpression of human A53T α-synuclein to investigate common pathways in the two different types of the PD mouse models. For more accurate quantification of mouse brain proteome, the proteins were quantified using the method of stable isotope labeling with amino acids in mammals. We identified a total of 8355 proteins from the two mouse models; â 6800 and â 7200 proteins from α-synuclein PFF-injected mice and human A53T α-synuclein transgenic mice, respectively. Through pathway analysis of the differentially expressed proteins common to both PD mouse models, it was discovered that the complement and coagulation cascade pathways were enriched in the PD mice compared to control animals. Notably, a validation study demonstrated that complement component 3 (C3)-positive astrocytes were increased in the ventral midbrain of the intrastriatal α-synuclein PFF-injected mice and C3 secreted from astrocytes could induce the degeneration of dopaminergic neurons. This is the first study that highlights the significance of the complement and coagulation pathways in the pathogenesis of PD through proteome analyses with two sophisticated mouse models of PD.

Original languageEnglish (US)
Pages (from-to)3428-3443
Number of pages16
JournalJournal of Proteome Research
Volume20
Issue number7
DOIs
StatePublished - Jul 2 2021

Keywords

  • Parkinson's disease
  • TetP-A53T α-synuclein transgenic mouse
  • astrocytes
  • complement and coagulation cascades
  • complement component 3 (C3)
  • dopaminergic neurons
  • mass spectrometry
  • stable isotope labeling with amino acids in mammals (SILAM)
  • α-synuclein
  • α-synuclein preformed fibrils

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)

Fingerprint

Dive into the research topics of 'Complement and Coagulation Cascades are Potentially Involved in Dopaminergic Neurodegeneration in α-Synuclein-Based Mouse Models of Parkinson's Disease'. Together they form a unique fingerprint.

Cite this