Biology subjects

Mona, D.

Publications and source records attributed to Mona, D..

3 recordsLinked to original sources

bioRxiv2019

Two new polymorphic structures of alpha-synuclein solved by cryo-electron microscopy

Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinsons disease (PD). We here report two new polymorphic atomic structures of alpha-synuclein fibrils termed polymorphs 2a and 2b, at 3.0 [A] and 3.4 [A] resolution, respectively. These polymorphs show a radically different structure compared to previously reported polymorphs. The new structures have a 10 nm fibril diameter and are composed of two protofilaments which interact via intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 (polymorph 2b). The non-amyloid component (NAC) region of alpha-synuclein is fully buried by previously non-described interactions with the N-terminus. A hydrophobic cleft, the location of familial PD mutation sites, and the nature of the protofilament interface now invite to formulate hypotheses about fibril formation, growth and stability. Impact statementTwo new polymorphic structures of recombinant human alpha-synuclein fibrils show striking differences to previous structures, while familial PD mutation sites remain crucial for protofilament interaction and fibril stability.

neuroscience↗

bioRxiv2018

Detailed structural orchestration of Lewy pathology in Parkinson’s disease as revealed by 3D multicolor STED microscopy

Post-translational modifications of alpha-synuclein (aSyn), particularly phosphorylation at Serine 129 (Ser129-p) and truncation of its C-terminus (CTT), have been implicated in Parkinsons disease (PD) pathology. To gain more insight in the relevance of Ser129-p and CTT aSyn under physiological and pathological conditions, we investigated their subcellular distribution patterns in normal aged and PD brains using highly-selective antibodies in combination with 3D multicolor STED microscopy. We show that CTT aSyn localizes in mitochondria in PD patients and controls, whereas the organization of Ser129-p in a cytoplasmic network is strongly associated with pathology. Nigral Lewy bodies show an onion skin-like architecture, with a structured framework of Ser129-p aSyn and neurofilaments encapsulating CTT aSyn in their core, which displayed high content of proteins and lipids by label-free CARS microscopy. The subcellular phenotypes of antibody-labeled pathology identified in this study provide evidence for a crucial role of Ser129-p aSyn in Lewy body formation.

neuroscience↗

bioRxiv2018

Cryo-EM structure of alpha-synuclein fibrils

Intracellular inclusions of alpha-synuclein are the neuropathological hallmark of progressive disorders called synucleinopathies. Alpha-synuclein fibrils are associated with transmissive cell-to-cell propagation of pathology. We report the structure of an alpha-synuclein fibril (residues 1-121) determined by cryo-electron microscopy at 3.4[A] resolution. Two protofilaments form a polar fibril composed of staggered {beta}-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50-57, containing three mutation sites associated with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft may have implications for fibril elongation, and inform the rational design of molecules for diagnosis and treatment of synucleinopathies.

neuroscience↗