Megadalton-sized Dityrosine Aggregates of α-Synuclein Retain High Degrees of Structural Disorder and Internal Dynamics.

Heterogeneous aggregates of the human protein α-synuclein (αSyn) are abundantly found in Lewy body inclusions of Parkinson's disease patients. While structural information on classical αSyn amyloid fibrils is available, little is known about the conformational properties of disease-relevant, non-canonical aggregates. Here, we analyze the structural and dynamic properties of megadalton-sized dityrosine adducts of αSyn that form in the presence of reactive oxygen species and cytochrome c, a proapoptotic peroxidase that is released from mitochondria during sustained oxidative stress. In contrast to canonical cross-ß amyloids, these aggregates retain high degrees of internal dynamics, which enables their characterization by solution-state NMR spectroscopy. We find that intermolecular dityrosine crosslinks restrict αSyn motions only locally whereas large segments of concatenated molecules remain flexible and disordered. Indistinguishable aggregates form in crowded in vitro solutions and in complex environments of mammalian cell lysates, where relative amounts of free reactive oxygen species, rather than cytochrome c, are rate limiting. We further establish that dityrosine adducts inhibit classical amyloid formation by maintaining αSyn in its monomeric form and that they are non-cytotoxic despite retaining basic membrane-binding properties. Our results suggest that oxidative αSyn aggregation scavenges cytochrome c's activity into the formation of amorphous, high molecular-weight structures that may contribute to the structural diversity of Lewy body deposits.

Molecular imaging insights into neurodegeneration: focus on α-synuclein radiotracers.

Neurodegenerative diseases characterized by the presence of α-synuclein-a hallmark of pathologic inclusions termed Lewy bodies-include Parkinson's disease, dementia with Lewy bodies, and multiple-system atrophy. Although motor symptoms are related to the altered presynaptic dopaminergic function in these diseases, the appearance of α-synuclein inclusions precedes the involvement of the nigrostriatal dopaminergic pathway. Hence, the most accurate and earliest definition of premotor Parkinson's disease ought to rely on imaging α-synuclein rather than dopaminergic changes. Moreover, dopaminergic imaging has been controversial in monitoring the effects of investigational disease-modifying drugs. For these clinical trials, intense interest in longitudinally imaging α-synuclein as the primary pathologic process has led to efforts toward developing a suitable radiotracer for this key protein. An overview of the present α-synuclein radiotracer development scenario is presented here.

Molecular Imaging Insights into Neurodegeneration: Focus on Tau PET Radiotracers.

Neurodegenerative diseases are characterized by progressive dysfunction and neuronal death, showing specific protein inclusions at autopsy. In vivo detection of these key proteins, namely amyloid-ß, tau, α-synuclein, and trans-active response DNA-binding protein 43 kDa, is possible by means of molecular neuroimaging techniques, such as PET. The development of selective PET radiotracers targeting these proteins is critical for early and accurate diagnosis and for the successful development of disease-modifying therapies. Selective PET radiotracers for amyloid-ß are already available, and potential tau tracers are emerging as new-generation biomarkers. An overview of the tau-PET radiotracer development scenario, focusing on tracers that are presently being examined in humans, is presented.

Resolving sentence ambiguity with planning and working memory resources: Evidence from fMRI.

We used functional magnetic resonance imaging (fMRI) to test competing claims about the role of executive resources during the disambiguation of a sentence featuring a temporary structural ambiguity. Written sentences with a direct object (DO) structure or a sentential complement (SC) structure were shown to 19 healthy, right-handed, young adults in a phrase-by-phrase manner. These sentences contained a main verb that is statistically more likely to be associated with a DO structure or an SC structure. Half of each type of sentence also contained an extra phrase strategically located to stress working memory prior to disambiguating the sentence. We found that sentences featuring a less consistent verb-structure mapping recruit greater dorsolateral prefrontal cortex (dlPFC) activation than sentences with a more consistent verb-structure mapping, implicating strategic on-line planning during resolution of a temporary structural ambiguity. By comparison, we observed left inferior parietal cortex (IPC) activation in sentences with an increased working memory demand compared to sentences with a low working memory load. These findings are consistent with a large-scale neural network for sentence processing that recruits distinct planning and working memory processing resources as needed to support the comprehension of sentences.