Publications by authors named "Alexandre Chappard"

Article Synopsis
  • Protein misfolding and aggregation into complex structures are common in neurodegenerative diseases, affecting conditions like Parkinson's.
  • Single-molecule techniques have improved the study of these rare protein aggregates, but they often require tagged proteins or non-specific dyes.
  • The researchers developed a method using high-affinity antibodies and advanced microscopy to specifically detect α-synuclein aggregates in low concentrations within biological samples.
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Protein misfolding and aggregation is a characteristic of many neurodegenerative disorders, including Alzheimer's and Parkinson's disease. The oligomers generated during aggregation are likely involved in disease pathogenesis and present promising biomarker candidates. However, owing to their small size and low concentration, specific tools to quantify and characterize aggregates in complex biological samples are still lacking.

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α-Synuclein (αSyn), a 140-residue intrinsically disordered protein, comprises the primary proteinaceous component of pathology-associated Lewy body inclusions in Parkinson's disease (PD). Due to its association with PD, αSyn is studied extensively; however, the endogenous structure and physiological roles of this protein are yet to be fully understood. Here, ion mobility-mass spectrometry and native top-down electron capture dissociation fragmentation have been used to elucidate the structural properties associated with a stable, naturally occurring dimeric species of αSyn.

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Article Synopsis
  • Protein misfolding and aggregation into structures like oligomers and fibrils are linked to various neurodegenerative diseases.
  • Traditional methods for studying these aggregates often lack specificity and rely on labeled proteins or non-specific stains.
  • The researchers developed a new technique using a high-affinity antibody with unique fluorophores and advanced microscopy to specifically identify and analyze α-synuclein aggregates in low concentrations, relevant to biological samples.
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Aggregation of alpha-synuclein (α-Syn) drives Parkinson's disease (PD), although the initial stages of self-assembly and structural conversion have not been directly observed inside neurons. In this study, we tracked the intracellular conformational states of α-Syn using a single-molecule Förster resonance energy transfer (smFRET) biosensor, and we show here that α-Syn converts from a monomeric state into two distinct oligomeric states in neurons in a concentration-dependent and sequence-specific manner. Three-dimensional FRET-correlative light and electron microscopy (FRET-CLEM) revealed that intracellular seeding events occur preferentially on membrane surfaces, especially at mitochondrial membranes.

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The aggregation of alpha-synuclein (α-SYN) follows a cascade of oligomeric, prefibrillar and fibrillar forms, culminating in the formation of Lewy Bodies (LB), the pathological hallmarks of Parkinson's Disease. Although LB contain over 70 proteins, the potential for interactions along the aggregation pathway of α-SYN is unknown. Here we propose a map of interactions of 65 proteins against different species of α-SYN.

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