Mechanistic aspects of Parkinson’s disease: α-synuclein and the biomembrane

Beyer, Klaus

doi:10.1007/s12013-007-0014-9

Cited by 96 publications

(105 citation statements)

References 150 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The DMPS peak shifts upfield by 0.3 ppm, and for DMPC a weaker upfield shift of 0.1 ppm is observed. The observation of an electrostatically driven Lit30-membrane interaction agrees well with studies on other vesicle binding disordered proteins, such as the T cell receptor (Sigalov and Hendricks, 2009), the viral genome-linked protein (Vpg) (Rantalainen et al, 2009), and a-synuclein (Davidson et al, 1998;Beyer, 2007). While Lti30 exhibits a weak affinity for neutral vesicles made of zwitterionic DOPC, presumably due to weak hydrophobic interactions, Lti30 also has a very pronounced interaction with lipids containing the negatively phosphatidic acid DOPA (data not shown).…”

Section: Solid-state 31 P Mas Nmr: Interaction Of Lti30 With Vesiclessupporting

confidence: 84%

Tunable Membrane Binding of the Intrinsically Disordered Dehydrin Lti30, a Cold-Induced Plant Stress Protein

et al. 2011

View full text Add to dashboard Cite

Dehydrins are intrinsically disordered plant proteins whose expression is upregulated under conditions of desiccation and cold stress. Their molecular function in ensuring plant survival is not yet known, but several studies suggest their involvement in membrane stabilization. The dehydrins are characterized by a broad repertoire of conserved and repetitive sequences, out of which the archetypical K-segment has been implicated in membrane binding. To elucidate the molecular mechanism of these K-segments, we examined the interaction between lipid membranes and a dehydrin with a basic functional sequence composition: Lti30, comprising only K-segments. Our results show that Lti30 interacts electrostatically with vesicles of both zwitterionic (phosphatidyl choline) and negatively charged phospholipids (phosphatidyl glycerol, phosphatidyl serine, and phosphatidic acid) with a stronger binding to membranes with high negative surface potential. The membrane interaction lowers the temperature of the main lipid phase transition, consistent with Lti30's proposed role in cold tolerance. Moreover, the membrane binding promotes the assembly of lipid vesicles into large and easily distinguishable aggregates. Using these aggregates as binding markers, we identify three factors that regulate the lipid interaction of Lti30 in vitro: (1) a pH dependent His on/off switch, (2) phosphorylation by protein kinase C, and (3) reversal of membrane binding by proteolytic digest.

show abstract

Section: Solid-state 31 P Mas Nmr: Interaction Of Lti30 With Vesiclessupporting

confidence: 84%

Tunable Membrane Binding of the Intrinsically Disordered Dehydrin Lti30, a Cold-Induced Plant Stress Protein

et al. 2011

View full text Add to dashboard Cite

show abstract

“…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: Discussionmentioning

confidence: 59%

“…To our knowledge, this evidence is the best to date for an αS aggregation pathway that involves a helical intermediate, and adds to indications that helical intermediates may be generally important in amyloid aggregation pathways. We propose that the TFE-induced αS intermediate may resemble membrane-associated conformations; therefore the TFE-induced aggregation pathway may be related to pathways of membrane-induced aggregation, which could be significant in vivo, where αS is known to bind to synaptic vesicles and possibly other membrane surfaces (16). We demonstrate that the formation of the TFE-induced intermediate is not significantly affected by any of the three PD-linked αS mutations, but that all three mutations do influence the overall rate of TFE fibril formation, indicating that the mutations exert their effects subsequent to the formation of the intermediate state.…”

Section: Discussionmentioning

confidence: 99%

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

“…The membrane interaction of ␣-synuclein has become of significant interest for the pathological as well as the physiological functions of this protein (4,5). Although its physiological roles are not fully understood, it is thought that ␣-synuclein binds to synaptic vesicles, plays a role in neuronal plasticity, modulates the release of neurotransmitters, plays a role in vesicular trafficking and affects brain lipid metabolism (6 -14).…”

Section: Several Familial Forms Of Parkinson Disease (Pd)mentioning

confidence: 99%

Membrane Curvature Induction and Tubulation Are Common Features of Synucleins and Apolipoproteins

Varkey

Isas

Mizuno

et al. 2010

Journal of Biological Chemistry

287

312

View full text Add to dashboard Cite

Synucleins and apolipoproteins have been implicated in a number of membrane and lipid trafficking events. Lipid interaction for both types of proteins is mediated by 11 amino acid repeats that form amphipathic helices. This similarity suggests that synucleins and apolipoproteins might have comparable effects on lipid membranes, but this has not been shown directly. Here, we find that ␣-synuclein, ␤-synuclein, and apolipoprotein A-1 have the conserved functional ability to induce membrane curvature and to convert large vesicles into highly curved membrane tubules and vesicles. The resulting structures are morphologically similar to those generated by amphiphysin, a curvature-inducing protein involved in endocytosis. Unlike amphiphysin, however, synucleins and apolipoproteins do not require any scaffolding domains and curvature induction is mediated by the membrane insertion and wedging of amphipathic helices alone. Moreover, we frequently observed that ␣-synuclein caused membrane structures that had the appearance of nascent budding vesicles. The ability to function as a minimal machinery for vesicle budding agrees well with recent findings that ␣-synuclein plays a role in vesicle trafficking and enhances endocytosis. Induction of membrane curvature must be under strict regulation in vivo; however, as we find it can also cause disruption of membrane integrity. Because the degree of membrane curvature induction depends on the concerted action of multiple proteins, controlling the local protein density of tubulating proteins may be important. How cellular safeguarding mechanisms prevent such potentially toxic events and whether they go awry in disease remains to be determined.

show abstract

Mechanistic aspects of Parkinson’s disease: α-synuclein and the biomembrane

Cited by 96 publications

References 150 publications

Tunable Membrane Binding of the Intrinsically Disordered Dehydrin Lti30, a Cold-Induced Plant Stress Protein

Tunable Membrane Binding of the Intrinsically Disordered Dehydrin Lti30, a Cold-Induced Plant Stress Protein

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

Membrane Curvature Induction and Tubulation Are Common Features of Synucleins and Apolipoproteins

Contact Info

Product

Resources

About