Selective loss of nigral dopamine neurons induced by overexpression of truncated human α-synuclein in mice

Wakamatsu, Masaki; Ishii, Aiko; Iwata, Satoru; Sakagami, Junko; Ukai, Yuriko; Ono, Mieko; Kanbe, Daiji; Muramatsu, Shin‐ichi; Kobayashi, Kazuto; Iwatsubo, Takeshi; Yoshimoto, Makoto

doi:10.1016/j.neurobiolaging.2006.11.017

Cited by 148 publications

(152 citation statements)

References 42 publications

Supporting

Mentioning

140

Contrasting

Unclassified

Order By: Relevance

“…We show that αS is likely to aggregate via such an intermediate in the presence of TFE, suggesting that membrane-induced αS aggregation may also involve the formation of a helical intermediate. Furthermore, TFE-induced fibrils are β-sheet rich and resemble previously reported aggregates formed by C terminally truncated αS (11), as well as structures induced by detergent and lipid interactions (12,13), which may be linked to PD initiation and progression (14)(15)(16)(17).…”

supporting

confidence: 80%

“…Also, while this paper was in review, a study was published which described detergent-induced formation of species that may be similar to our TFE fibrils (13). Although more research must be done to evaluate whether species produced by truncation mutations and/or lipid and detergent interactions are indeed related to TFE fibrils, the potential similarities with previously observed structures are particularly important in light of the hypothesis that intermediate or alternative oligomeric or fibrillar species are responsible for PD toxicity (23), recent findings that C-terminal truncation of αS can lead to neuron loss and increased susceptibility to stress in transgenic mouse models (14,15), and multiple lines of evidence that potentially link lipid interactions and metabolism with PD etiology (16).…”

Section: Discussionsupporting

confidence: 55%

See 1 more Smart Citation

Identification of a helical intermediate in trifluoroethanol-induced alpha-synuclein aggregation

Anderson

Ramlall

Rospigliosi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

161

171

View full text Add to dashboard Cite

Because oligomers and aggregates of the protein α-synuclein (αS) are implicated in the initiation and progression of Parkinson's disease, investigation of various αS aggregation pathways and intermediates aims to clarify the etiology of this common neurodegenerative disorder. Here, we report the formation of short, flexible, β-sheet-rich fibrillar species by incubation of αS in the presence of intermediate (10-20% v∕v) concentrations of 2,2,2-trifluoroethanol (TFE). We find that efficient production of these TFE fibrils is strongly correlated with the TFE-induced formation of a monomeric, partly helical intermediate conformation of αS, which exists in equilibrium with the natively disordered state at low [TFE] and with a highly α-helical conformation at high [TFE]. This partially helical intermediate is on-pathway to the TFE-induced formation of both the highly helical monomeric conformation and the fibrillar species. TFE-induced conformational changes in the monomer protein are similar for wild-type αS and the C-terminal truncation mutant αS1-102, indicating that TFE-induced structural transitions involve the N terminus of the protein. Moreover, the secondary structural transitions of three Parkinson's disease-associated mutants, A30P, A53T, and E46K, are nearly identical to wild-type αS, but oligomerization rates differ substantially among the mutants. Our results add to a growing body of evidence indicating the involvement of helical intermediates in protein aggregation processes. Given that αS is known to populate both highly and partially helical states upon association with membranes, these TFE-induced conformations imply relevant pathways for membrane-induced αS aggregation both in vitro and in vivo.is one of a number of synucleopathies in which aggregation of the protein α-Synuclein (αS) is linked to pathogenesis (1). αS is intrinsically disordered, but in the presence of lipid or detergent vesicles or micelles, adopts a highly helical structure in which its N-terminal region is membrane-bound and the C-terminal tail remains predominantly free and unstructured (2, 3). Although most PD cases are sporadic or idiopathic, three point mutations of α-Synuclein-A53T, A30P, and E46K-are associated with familial and early-onset disease (see Review (4)).In addition to its free and membrane-bound states, αS adopts partially structured intermediate conformations under low-pH or high-temperature conditions (5). A folding intermediate has also been detected at low [TFE] (6). Conditions favoring the formation of these intermediates also promote amyloid fibril growth, possibly implicating intermediate conformers as key species in the aggregation pathways.Here, we examine TFE-induced monomer conformational changes, oligomerization, and fibrillization in detail for wild-type (WT) αS, C terminally truncated WT αS (αS102), and the PDassociated αS mutants A30P, A53T, and E46K, expanding upon previous studies by Munishkina, et. al. (6) and Li, et. al. (7). This research also complements our previous fluorescence correlatio...

show abstract

supporting

confidence: 80%

Section: Discussionsupporting

confidence: 55%

Identification of a helical intermediate in trifluoroethanol-induced alpha-synuclein aggregation

Anderson

Ramlall

Rospigliosi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

161

171

View full text Add to dashboard Cite

show abstract

“…Thus, the model lacks a cardinal feature of PD, but reveals a progressive process of terminal loss. This observation is not unusual for mouse models of neurodegenerative diseases, and dopaminergic cell loss has been reported in only 2 of the many mouse models over-expressing alphasynuclein, a line expressing a doubly mutated protein, which is not found in patients and in a line expressing a truncated alpha-synuclein [36,37]. Similarly most other mouse models of PD based on disease-causing mutations also lack dopaminergic cell death, although a conditional model of Parkin deletion has recently been reported to show progressive loss of dopaminergic neurons, suggesting that early deletion of the gene elicits compensatory mechanisms [18,38].…”

Section: Thy1-asyn Mice Exhibit a Progressive Loss Of Striatal Dopaminementioning

confidence: 96%

A Progressive Mouse Model of Parkinson's Disease: The Thy1-aSyn (“Line 61”) Mice

et al. 2012

View full text Add to dashboard Cite

Identification of mutations that cause rare familial forms of Parkinson's disease (PD) and subsequent studies of genetic risk factors for sporadic PD have led to an improved understanding of the pathological mechanisms that may cause nonfamilial PD. In particular, genetic and pathological studies strongly suggest that alpha-synuclein, albeit very rarely mutated in PD patients, plays a critical role in the vast majority of individuals with the sporadic form of the disease. We have extensively characterized a mouse model over-expressing full-length, human, wild-type alpha-synuclein under the Thy-1 promoter. We have also shown that this model reproduces many features of sporadic PD, including progressive changes in dopamine release and striatal content, alphasynuclein pathology, deficits in motor and nonmotor functions that are affected in pre-manifest and manifest phases of PD, inflammation, and biochemical and molecular changes similar to those observed in PD. Preclinical studies have already demonstrated improvement with promising new drugs in this model, which provides an opportunity to test novel neuroprotective strategies during different phases of the disorder using endpoint measures with high power to detect drug effects.

show abstract

“…Analysis of ␣Syn fibrils revealed that the region encompassing amino acids 32-102 is involved in the formation of the fibril core (21). Although the C-terminal acidic region is not part of the ␣Syn fibril core, deletion of the C-terminal region significantly promotes ␣Syn aggregation in vitro and in mice (22)(23)(24)(25)(26). Therefore, the C-terminal region plays a role in regulating ␣Syn aggregation.…”

mentioning

confidence: 99%

Residue Histidine 50 Plays a Key Role in Protecting α-Synuclein from Aggregation at Physiological pH

Chi

Armstrong

Jones

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Mutations of ␣-synuclein (␣Syn) can cause early-onset familial Parkinson disease (PD). Results: The H50Q, H50D, or H50A substitution promotes, whereas the H50R substitution inhibits, ␣Syn aggregation in vitro. Conclusion:The recently identified PD-causing ␣Syn mutant, ␣Syn(H50Q), accelerates ␣Syn aggregation. Significance: The partial positive charge of His-50 at physiological pH likely plays a role in suppressing ␣Syn aggregation.

show abstract

Selective loss of nigral dopamine neurons induced by overexpression of truncated human α-synuclein in mice

Cited by 148 publications

References 42 publications

Identification of a helical intermediate in trifluoroethanol-induced alpha-synuclein aggregation

Identification of a helical intermediate in trifluoroethanol-induced alpha-synuclein aggregation

A Progressive Mouse Model of Parkinson's Disease: The Thy1-aSyn (“Line 61”) Mice

Residue Histidine 50 Plays a Key Role in Protecting α-Synuclein from Aggregation at Physiological pH

Contact Info

Product

Resources

About