Mechanisms of alpha-synuclein spread in mouse and human models of Parkinson's disease
Abstract/Contents
- Abstract
- Parkinson's disease (PD) - the second most common neurodegenerative disorder - is characterized by the progressive loss of dopaminergic neurons in the Substantia nigra pars compacta (SNpc), which result in motor symptoms that include rigidity, postural instability, tremor at rest and bradykinesia. A key histopathological hallmark of Parkin-son's disease is the presence of protein accumulations called Lewy Bodies that are, in part, composed of the protein alpha-synuclein. Accruing evidence suggests that alpha-synuclein pathology can propagate through neuronal circuits in the brain, contributing to the progressive nature of the disease. Similar prion-like properties have also been attributed to proteins aggregating in other neurodegenerative diseases including Amyloid beta and Tau in Alzheimer's disease. Thus, it is therapeutically pertinent to identify modifiers of protein aggregation and transmission as potential targets to slow down neurodegenerative disease progression. A growing number of genetic mutations and risk factors have been identified in studies of familial and sporadic forms of PD. However, how these genes affect alpha-synuclein aggregation and pathological transmission, and whether they can be targeted for therapeutic interventions, remains unclear. We performed a targeted screen of risk genes associated with PD and parkinsonism for modifiers of alpha-synuclein aggregation, using an alpha-synuclein pre-formed-fibril (PFF) induction assay. We found that decreased expression of Leucine-rich repeat kinase 2 (Lrrk2) and β-Glucocerebrosidase (Gba) modulated alpha-synuclein aggregation in mouse primary neurons. Conversely, alpha-synuclein aggregation increased in primary neurons carrying the PD-linked LRRK2 G2019S mutation. In vivo, using LRRK2 G2019S trans-genic mice, we observed acceleration of alpha-synuclein aggregation and degeneration of dopaminergic neurons in the SNpc, exacerbated degeneration-associated neuroinflammation and motor behavioral deficits. Histopathological studies provide strong evidence for spreading of alpha-synuclein pathology in the human brain. However, our ability to investigate alpha-synuclein spreading in human neurons is limited. Thus, we established a novel human alpha-synuclein transmission model using induced pluripotent stem cell (iPS)-derived neurons (iNs), where human alpha-synuclein PFFs triggered aggregation of endogenous alpha-synuclein in a time-dependent manner. In PD subject-derived iNs, the G2019S mutation enhanced alpha-synuclein aggregation, whereas loss of LRRK2 decreased aggregation. Collectively, these findings demonstrate a strong interaction be-tween the PD risk gene LRRK2 and alpha-synuclein and raise the possibility that targeting LRRK2 may be broadly effective in PD, extending beyond cases caused by mutations in this gene. Lastly, we combined the iDISCO (immunolabeling-enabled three-dimensional imaging of solvent-cleared organs) brain clearing technique with novel analysis tools to visualize and quantify alpha-synuclein accumulation in an unbiased and comprehensive way at a whole brain-wide scale. We mapped the progression and spreading pattern of alpha-synuclein in the adult mouse brain longitudinally into old age following intra-striatal PFF delivery, and observed a rapid accumulation of alpha-synuclein in both hemisphere including brain structures critically implicated in PD. We believe these tools and analyses can be broadly applied to track the prion-like spread of other neurodegenerative disease proteins throughout the adult nervous system.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2019; ©2019 |
| Publication date | 2019; 2019 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Bieri, Gregor |
|---|---|
| Degree supervisor | Gitler, Aaron D |
| Thesis advisor | Gitler, Aaron D |
| Thesis advisor | Brunet, Anne, 1972- |
| Thesis advisor | Wang, Xinnan |
| Thesis advisor | Wyss-Coray, Anton |
| Degree committee member | Brunet, Anne, 1972- |
| Degree committee member | Wang, Xinnan |
| Degree committee member | Wyss-Coray, Anton |
| Associated with | Stanford University, Neurosciences Program. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Gregor Bieri. |
|---|---|
| Note | Submitted to the Neurosciences Program. |
| Thesis | Thesis Ph.D. Stanford University 2019. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2019 by Gregor Bieri
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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