Targeting the Chameleon: a Focused Look at α-Synuclein and Its Roles in Neurodegeneration

Silva, Blanca A.; Breydo, Leonid; Uversky, Vladimir N.

doi:10.1007/s12035-012-8334-1

Cited by 24 publications

(21 citation statements)

References 177 publications

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“…Similarly as chameleons change color to mimic their environment, protein chameleons have high structural plasticity and are able to adopt various conformations in a template-dependent manner [19]. Although the intrinsically disordered SYN is predominantly unfolded at physiological conditions, in response to changes in its environment it is capable of adopting structurally unrelated conformations ranging from intrinsically disordered form to various partially folded conformations with different contents of secondary structural elements induced by low pH, high temperature, organic solvents, membranes, agrochemicals, or metal ions [19,20]. The structural properties of SYN have been extensively characterized under a variety of conditions [21][22][23][24][25][26][27][28][29].…”

Section: U N C O R R E C T E D P R O O Fmentioning

confidence: 99%

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

Szénási¹,

Oláh²,

Szabó³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The hallmarks of Parkinson's disease and other synucleinopathies, Tubulin Polymerization Promoting Protein (TPPP/p25) and α-synuclein (SYN) have two key features: they are disordered and co-enriched/co-localized in brain inclusions. These Neomorphic Moonlighting Proteins display both physiological and pathological functions due to their interactions with distinct partners. To achieve the selective targeting of the pathological TPPP/p25-SYN but not the physiological TPPP/ p25-tubulin complex, their interfaces were identified as a specific innovative strategy for the development of anti-Parkinson drugs. Therefore, the interactions of TPPP/p25 with tubulin and SYN were characterized which suggested the involvements of the 178-187 aa and 147-156 aa segments in the complexation of TPPP/p25 with tubulin and SYN, respectively. However, various truncated and deletion mutants reduced but did not abolish the interactions except one mutant; in addition synthetized fragments corresponding to the potential binding segments of TPPP/p25 failed to interact with SYN. In fact, the studies of the multiple interactions at molecular and cellular levels revealed the high conformational plasticity, chameleon feature, of TPPP/p25 that ensures exceptional functional resilience; the lack of previously identified binding segments could be replaced by other segments. The experimental results are underlined by distinct bioinformatics tools. All these data revealed that although targeting chameleon proteins is a challenging task, nevertheless, the validation of a drug target can be achieved by identifying the interface of complexes of the partner proteins existing at the given pathological conditions.

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Section: U N C O R R E C T E D P R O O Fmentioning

confidence: 99%

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

Szénási¹,

Oláh²,

Szabó³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Another apolipoprotein-related protein, α-synuclein (described by Uversky in Chap. 2 of this volume), is also intrinsically disordered in solution, acquires an amphipathic α-helical structure upon binding to a lipid bilayer, and can form extracellular β-sheet rich amyloid deposits in neurodegenerative diseases such as Parkinson’s (Silva et al 2013). …”

Section: 2 Apolipoproteins In Amyloid Diseasesmentioning

confidence: 99%

Amyloid-Forming Properties of Human Apolipoproteins: Sequence Analyses and Structural Insights

Das

Gursky

2015

Advances in Experimental Medicine and Biology

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Apolipoproteins are protein constituents of lipoproteins that transport cholesterol and fat in circulation and are central to cardiovascular health and disease. Soluble apolipoproteins can transiently dissociate from the lipoprotein surface in a labile free form that can misfold, potentially leading to amyloid disease. Misfolding of apoA-I, apoA-II, and serum amyloid A (SAA) causes systemic amyloidoses, apoE4 is a critical risk factor in Alzheimer's disease, and apolipoprotein misfolding is also implicated in cardiovascular disease. To explain why apolipoproteins are overrepresented in amyloidoses, it was proposed that the amphipathic α-helices, which form the lipid surface-binding motif in this protein family, have high amyloid-forming propensity. Here, we use 12 sequence-based bioinformatics approaches to assess amyloid-forming potential of human apolipoproteins and to identify segments that are likely to initiate β-aggregation. Mapping such segments on the available atomic structures of apolipoproteins helps explain why some of them readily form amyloid while others do not. Our analysis shows that nearly all amyloidogenic segments: (i) are largely hydrophobic, (ii) are located in the lipid-binding amphipathic α-helices in the native structures of soluble apolipoproteins, (iii) are predicted in both native α-helices and β-sheets in the insoluble apoB, and (iv) are predicted to form parallel in-register β-sheet in amyloid. Most of these predictions have been verified experimentally for apoC-II, apoA-I, apoA-II and SAA. Surprisingly, the rank order of the amino acid sequence propensity to form amyloid (apoB > apoA-II > apoC-II ≥ apoA-I, apoC-III, SAA, apoC-I > apoA-IV, apoA-V, apoE) does not correlate with the proteins' involvement in amyloidosis. Rather, it correlates directly with the strength of the protein-lipid association, which increases with increasing protein hydrophobicity. Therefore, the lipid surface-binding function and the amyloid-forming propensity are both rooted in apolipoproteins' hydrophobicity, suggesting that functional constraints make it difficult to completely eliminate pathogenic apolipoprotein misfolding. We propose that apolipoproteins have evolved protective mechanisms against misfolding, such as the sequestration of the amyloidogenic segments via the native protein-lipid and protein-protein interactions involving amphipathic α-helices and, in case of apoB, β-sheets. KeywordsLipid transport; Systemic amyloidosis; Atherosclerosis and Alzheimer's disease; Atomic protein structure; Sequence-based prediction algorithms Correspondence to: Olga Gursky. HHS Public AccessAuthor manuscript Adv Exp Med Biol. Author manuscript; available in PMC 2017 September 24.Published in final edited form as:Adv Exp Med Biol. 2015 ; 855: 175-211. doi:10.1007/978-3-319-17344-3_8. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript Lipoproteins and Apolipoproteins in Lipid Transport and MetabolismLipids in plasma, lymph and cerebrospinal fluid are transported via lipoproteins that are...

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“…Alzheimer's disease | Parkinson's disease | dementia with Lewy bodies | chemical kinetics | amyloid fibrils A lzheimer's disease (AD) and Parkinson's disease (PD) have been closely associated with the misfolding and aggregation of Aβ into amyloid plaques and of α-synuclein into Lewy bodies, respectively (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). In other situations, as for example in the case of dementia with Lewy bodies (DLB), amyloid plaques and Lewy bodies are observed together, and parts of the sequence of α-synuclein are found to constitute the nonamyloid component (NAC) of amyloid plaques (13)(14)(15)(16)(17).…”

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confidence: 99%

Monomeric and fibrillar α-synuclein exert opposite effects on the catalytic cycle that promotes the proliferation of Aβ42 aggregates

Chia

Flagmeier

Habchi

et al. 2017

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

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The coaggregation of the amyloid-β peptide (Aβ) and α-synuclein is commonly observed in a range of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. The complex interplay between Aβ and α-synuclein has led to seemingly contradictory results on whether α-synuclein promotes or inhibits Aβ aggregation. Here, we show how these conflicts can be rationalized and resolved by demonstrating that different structural forms of α-synuclein exert different effects on Aβ aggregation. Our results demonstrate that whereas monomeric α-synuclein blocks the autocatalytic proliferation of Aβ42 (the 42-residue form of Aβ) fibrils, fibrillar α-synuclein catalyses the heterogeneous nucleation of Aβ42 aggregates. It is thus the specific balance between the concentrations of monomeric and fibrillar α-synuclein that determines the outcome of the Aβ42 aggregation reaction.

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Targeting the Chameleon: a Focused Look at α-Synuclein and Its Roles in Neurodegeneration

Cited by 24 publications

References 177 publications

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

Amyloid-Forming Properties of Human Apolipoproteins: Sequence Analyses and Structural Insights

Monomeric and fibrillar α-synuclein exert opposite effects on the catalytic cycle that promotes the proliferation of Aβ42 aggregates

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