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Insight into ?-synuclein plasticity and misfolding from differential micelle binding.

ABSTRACT: Misfolded species of the 140-residue protein ?-synuclein (?S) are implicated in the demise of dopaminergic neurons, resulting in fatal neurodegeneration. The intrinsically unstructured protein binds curved synaptic vesicle membranes in helical conformations but misfolds into amyloid fibrils via ?-sheet interactions. Breaks in helical ?S conformation may offer a pathway to transition from helical to sheet conformation. Here, we explore the evolution of broken ?S helix conformations formed in complex with SDS and SLAS micelles by molecular dynamics simulations. The population distribution of experimentally observed ?S conformations is related to the spatial concentration of intrinsic micelle shape perturbations. For the success of micelle-induced ?S folding, we posit the length of the first helical segment formed, which controls micelle ellipticity, to be a key determinant. The degree of micelle curvature relates to the arrangement and segmental motions of helical secondary structure elements. A criterion for assessing the reproduction of such intermediate time scale protein dynamics is introduced by comparing the sampling of experimental and simulated spin label distributions. Finally, at the sites of breaks in the elongated, marginally stable ?S helix, vulnerability to forming a transient, intramolecular ?-sheet is identified. Upon subsequent intermolecular ?-sheet pairing, pathological ?S amyloid formation from initial helical conformation is thus achievable.

SUBMITTER: Mazumder P

PROVIDER: S-EPMC3946565 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Insight into α-synuclein plasticity and misfolding from differential micelle binding.

Mazumder Parichita P Suk Jae-Eun JE Ulmer Tobias S TS

The journal of physical chemistry. B 20130912 39

Misfolded species of the 140-residue protein α-synuclein (αS) are implicated in the demise of dopaminergic neurons, resulting in fatal neurodegeneration. The intrinsically unstructured protein binds curved synaptic vesicle membranes in helical conformations but misfolds into amyloid fibrils via β-sheet interactions. Breaks in helical αS conformation may offer a pathway to transition from helical to sheet conformation. Here, we explore the evolution of broken αS helix conformations formed in comp ...[more]

PMID: 23978162

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Project description:BACKGROUND:Prior studies in C. elegans demonstrated that the expression of aggregation-prone polyglutamine proteins in muscle wall cells compromised the folding of co-expressed temperature-sensitive proteins, prompting interest in whether the accumulation of a misfolded protein in pathologic features of human neurodegenerative disease burdens cellular proteostatic machinery in a manner that impairs the folding of other cellular proteins. METHODS:Mice expressing high levels of mutant forms of tau and ?-synuclein (?Syn), which develop inclusion pathologies of the mutant protein in brain and spinal cord, were crossed to mice expressing low levels of mutant superoxide dismutase 1 fused to yellow fluorescent protein (G85R-SOD1:YFP) for aging and neuropathological evaluation. RESULTS:Mice expressing low levels of G85R-SOD1:YFP, alone, lived normal lifespans and were free of evidence of inclusion pathology, setting the stage to use this protein as a reporter of proteostatic function. We observed robust induction of G85R-SOD1:YFP inclusion pathology in the neuropil of spinal cord and brainstem of bigenic mice that co-express high levels of mutant tau in the spinal axis and develop robust spinal tau pathology (JNPL3 mice). In contrast, in crosses of the G85R-SOD1:YFP mice with mice that model spinal ?-synucleinopathy (the M83 model of ?Syn pathology), we observed no G85R-SOD1:YFP inclusion formation. Similarly, in crosses of the G85R-SOD1:YFP mice to mice that model cortical tau pathology (rTg4510 mice), we did not observe induction of G85R-SOD1:YFP inclusions. CONCLUSION:Despite robust burdens of neurodegenerative pathology in M83 and rTg4510 mice, the introduction of the G85R-SOD1:YFP protein was induced to aggregate only in the context of spinal tau pathology present in the JNPL3 model. These findings suggest unexpected specificity, mediated by both the primary protein pathology and cellular context, in the induced "secondary aggregation" of a mutant form of SOD1 that could be viewed as a reporter of proteostatic function.

Project description:α-Synuclein is the major pathological component of synucleinopathies including Parkinson's disease and dementia with Lewy bodies. Recent studies have demonstrated that α-synuclein also plays important roles in the release of synaptic vesicles and synaptic membrane recycling in healthy neurons. However, the precise relationship between the pathogenicity and physiological functions of α-synuclein remains to be elucidated. To address this issue, we investigated the subcellular localization of α-synuclein in normal and pathological conditions using primary mouse hippocampal neuronal cultures. While some neurons expressed high levels of α-synuclein in presynaptic boutons and cell bodies, other neurons either did not or only very weakly expressed the protein. These α-synuclein-negative cells were identified as inhibitory neurons by immunostaining with specific antibodies against glutamic acid decarboxylase (GAD), parvalbumin, and somatostatin. In contrast, α-synuclein-positive synapses were colocalized with the excitatory synapse marker vesicular glutamate transporter-1. This expression profile of α-synuclein was conserved in the hippocampus in vivo. In addition, we found that while presynaptic α-synuclein colocalizes with synapsin, a marker of presynaptic vesicles, it is not essential for activity-dependent membrane recycling induced by high potassium treatment. Exogenous supply of preformed fibrils generated by recombinant α-synuclein was shown to promote the formation of Lewy body (LB) -like intracellular aggregates involving endogenous α-synuclein. GAD-positive neurons did not form LB-like aggregates following treatment with preformed fibrils, however, exogenous expression of human α-synuclein allowed intracellular aggregate formation in these cells. These results suggest the presence of a different mechanism for regulation of the expression of α-synuclein between excitatory and inhibitory neurons. Furthermore, α-synuclein expression levels may determine the efficiency of intracellular aggregate formation in different neuronal subtypes.

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Insight into ?-synuclein plasticity and misfolding from differential micelle binding.

Publications

Insight into α-synuclein plasticity and misfolding from differential micelle binding.

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