Lewy body | EPFL Graph Search

Lewy bodies are the inclusion bodies – abnormal aggregations of protein – that develop inside nerve cells affected by Parkinson's disease (PD), the Lewy body dementias (Parkinson's disease dementia and dementia with Lewy bodies (DLB)), and some other disorders. They are also seen in cases of multiple system atrophy, particularly the parkinsonian variant (MSA-P). Lewy bodies appear as spherical masses in the cytoplasm that displace other cell components. For instance, some Lewy bodies tend to displace the nucleus to one side of the cell. There are two main kinds of Lewy bodies: classical and cortical. Lewy bodies may be found in the midbrain (within the substantia nigra) or within the cortex. A classical Lewy body is an eosinophilic cytoplasmic inclusion consisting of a dense core surrounded by a halo of 10 nm wide radiating fibrils, the primary structural component of which is alpha-synuclein. In 1910, Fritz Heinrich Lewy was studying in Berlin for his doctorate. He was the first doctor to notice some unusual proteins in the brain, comparing them to earlier findings by Gonzalo Rodríguez Lafora. In 1913, Lafora described another case, and acknowledged Lewy as the discoverer, naming them cuerpos intracelulares de Lewy (intracellular Lewy bodies). Konstantin Nikolaevich Trétiakoff found them in 1919 in the substantia nigra of PD brains, called them corps de Lewy and is credited with the eponym. In 1923, Lewy published his findings in a book, The Study on Muscle Tone and Movement. Including Systematic Investigations on the Clinic, Physiology, Pathology, and Pathogenesis of Paralysis agitans. Eliasz Engelhardt, who is in the neurology department at Federal University of Rio de Janeiro, argued in 2017 that Lafora should be credited with the eponym, because he named them six years before Trétiakoff. Nonetheless, Trétiakoff is still the primary figure acknowledged for coining the term, “Lewy bodies.” According to the Journal of the History of the Neurosciences, Dr.

Towards elucidating the structural and cellular determinants of a-synuclein seeding and toxicity

Somanath Jagannath

Although it has been nearly two and half decades since the discovery of alpha-synuclein (aSyn) as the major component of Lewy bodies (LBs), our understanding of the involvement of different aSyn species, their seeding, spreading and toxicity in Parkinson's disease (PD) is limited. One of the major causes underlying this knowledge gap is the unavailability of adequate tools, techniques, and model systems to capture, monitor, and evaluate the role of different aSyn species in the disease process. In addition, our understanding of cell-type specific contributions to disease pathogenesis is limited. In this thesis, we systematically address the current knowledge gaps and elucidate the structural and cellular determinants of aSyn seeding and toxicity using cellular and animal model systems of PD. In the first chapter of this thesis, we describe an antibody characterization and validation pipeline to assess the specificity of antibodies to well-characterized preparations of various aSyn species, including monomers, fibrils, and different type of oligomers. Using an array of techniques, we demonstrate that that: i) none of the antibodies tested are specific for one particular type of aSyn species, including monomers, oligomers or fibrils; ii) all antibodies that were reported to be oligomer-specific also recognized fibrillar aSyn; and iii) a few antibodies (e.g., the antibody clone 26F1, 5G4) showed high specificity for oligomers and fibrils but did not bind to monomers. These findings suggest that most aSyn aggregate-specific antibodies cannot be used to differentiate between oligomers and fibrils, thus highlighting the importance of exercising caution when interpreting results obtained using these antibodies. In the second chapter of this thesis, we systematically addressed the current knowledge gaps on the role of aSyn oligomers in the initiation, seeding and pathology spreading. Towards this goal, we used different biophysical approaches to investigate aSyn seeding in vitro and in neurons and animal models of aSyn seeding and pathology spreading. we observed that oligomeric forms do not form in the PFF-based neuronal seeding model and we report that different types of oligomers do not seed pathology in vitro and primary hippocampal neurons, and their presence slows rather than accelerates aSyn fibrillization. Altogether, our work points to fibrils as the most seeding competent species and suggests that they are the critical mediators of pathology spreading in PD and other synucleinopathies.In the third chapter of this thesis, we used single-nuclei RNA-sequencing to investigate transcriptional changes in different cell types of the amygdala brain region, which is highly susceptible to developing pS129 positive aggregates in the PD brains. We identified that most of the top 100 differentially expressed genes (DEGs) are of neuronal rather than non-neuronal cell types. In addition, we report that the gene expression profile of a handful of PD risk genes such as Sncaip, Park7, Maob, Hspa8, Scl2a3 and Hsf3 and some pathways that have been associated with PD are differentially altered in specific cell types. Our study highlights the involvement of unique gene expression changes and their associated pathways in different cell types in driving the disease process at an early stage in a PFF-based mouse model of PD.

EPFL2022

Inhibition of alpha-synuclein fibrillization by dopamine is mediated by interactions with five C-terminal residues and with E83 in the NAC region

Hilal Lashuel, Adrian Schmid, Paolo Carloni, Alessandra Chesi

The interplay between dopamine and alpha-synuclein (AS) plays a central role in Parkinson's disease (PD). PD results primarily from a severe and selective devastation of dopaminergic neurons in substantia nigra pars compacta. The neuropathological hallmark of the disease is the presence of intraneuronal proteinaceous inclusions known as Lewy bodies within the surviving neurons, enriched in filamentous AS. In vitro, dopamine inhibits AS fibril formation, but the molecular determinants of this inhibition remain obscure. Here we use molecular dynamic (MD) simulations to investigate the binding of dopamine and several of its derivatives onto conformers representative of an NMR ensemble of AS structures in aqueous solution. Within the limitations inherent to MD simulations of unstructured proteins, our calculations suggest that the ligands bind to the (125)YEMPS(129) region, consistent with experimental findings. The ligands are further stabilized by long-range electrostatic interactions with glutamate 83 (E83) in the NAC region. These results suggest that by forming these interactions with AS, dopamine may affect AS aggregation and fibrillization properties. To test this hypothesis, we investigated in vitro the effects of dopamine on the aggregation of mutants designed to alter or abolish these interactions. We found that point mutations in the (125)YEMPS(129) region do not affect AS aggregation, which is consistent with the fact that dopamine interacts non-specifically with this region. In contrast, and consistent with our modeling studies, the replacement of glutamate by alanine at position 83 (E83A) abolishes the ability of dopamine to inhibit AS fibrillization.

Public Library of Science2008

Towards elucidating the structural and cellular determinants of a-synuclein seeding and toxicity

Somanath Jagannath

EPFL2022