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Full-Text Articles in Medicine and Health Sciences
Α-Synuclein Fibrils As Penrose Machines: A Chameleon In The Gear, Francesca De Giorgi, Vladimir N. Uversky, François Ichas
Α-Synuclein Fibrils As Penrose Machines: A Chameleon In The Gear, Francesca De Giorgi, Vladimir N. Uversky, François Ichas
Molecular Medicine Faculty Publications
In 1957, Lionel Penrose built the first man-made self-replicating mechanical device and illustrated its function in a series of machine prototypes, prefiguring our current view of the genesis and the proliferation of amyloid fibrils. He invented and demonstrated, with the help of his son Roger, the concepts that decades later, would become the fundamentals of prion and prion-like neurobiology: nucleation, seeding and conformational templating of monomers, linear polymer elongation, fragmentation, and spread. He published his premonitory discovery in a movie he publicly presented at only two conferences in 1958, a movie we thus reproduce here. By making a 30-year-jump in …
Ferritinophagy And Α-Synuclein: Pharmacological Targeting Of Autophagy To Restore Iron Regulation In Parkinson’S Disease, Matthew K. Boag, Angus Roberts, Vladimir N. Uversky, Linlin Ma, Des R. Richardson, Dean L. Pountney
Ferritinophagy And Α-Synuclein: Pharmacological Targeting Of Autophagy To Restore Iron Regulation In Parkinson’S Disease, Matthew K. Boag, Angus Roberts, Vladimir N. Uversky, Linlin Ma, Des R. Richardson, Dean L. Pountney
Molecular Medicine Faculty Publications
A major hallmark of Parkinson’s disease (PD) is the fatal destruction of dopaminergic neurons within the substantia nigra pars compacta. This event is preceded by the formation of Lewy bodies, which are cytoplasmic inclusions composed of α-synuclein protein aggregates. A triad contribution of α-synuclein aggregation, iron accumulation, and mitochondrial dysfunction plague nigral neurons, yet the events underlying iron accumulation are poorly understood. Elevated intracellular iron concentrations up-regulate ferritin expression, an iron storage protein that provides cytoprotection against redox stress. The lysosomal degradation pathway, autophagy, can release iron from ferritin stores to facilitate its trafficking in a process termed ferritinophagy. Aggregated …
Looking At The Recent Advances In Understanding Α-Synuclein And Its Aggregation Through The Proteoform Prism, Vladimir N. Uversky
Looking At The Recent Advances In Understanding Α-Synuclein And Its Aggregation Through The Proteoform Prism, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Despite attracting the close attention of multiple researchers for the past 25 years, α-synuclein continues to be an enigma, hiding sacred truth related to its structure, function, and dysfunction, concealing mechanisms of its pathological spread within the affected brain during disease progression, and, above all, covering up the molecular mechanisms of its multipathogenicity, i.e. the ability to be associated with the pathogenesis of various diseases. The goal of this article is to present the most recent advances in understanding of this protein and its aggregation and to show that the remarkable structural, functional, and dysfunctional multifaceted nature of α-synuclein can …
A Hyperbranched Dopamine-Containing Peg-Based Polymer For The Inhibition Of Α-Synuclein Fibrillation, Leonid Breydo, Ben Newland, Hong Zhang, Anne Rosser, Carsten Werner, Vladimir N. Uversky, Wenxin Wang
A Hyperbranched Dopamine-Containing Peg-Based Polymer For The Inhibition Of Α-Synuclein Fibrillation, Leonid Breydo, Ben Newland, Hong Zhang, Anne Rosser, Carsten Werner, Vladimir N. Uversky, Wenxin Wang
Molecular Medicine Faculty Publications
Aggregation of α-synuclein is believed to play an important role in Parkinson's disease and in other neurodegenerative maladies. Small molecule inhibitors of this process are among the most promising drug candidates for neurodegenerative diseases. Dendrimers have also been studied for anti-fibrillation applications but they can be difficult and expensive to synthetize. Here we show that RAFT polymerization can be used to produce a hyperbranched polyethylene glycol structure via a one-pot reaction. This polymer included a dopamine moiety, a known inhibitor of α-synuclein fibril formation. Dopamine within the polymer structure was capable of aggregation inhibition, although not to the same degree …
Calbindin-D28k Acts As A Calcium-Dependent Chaperone Suppressing Α-Synuclein Fibrillation In Vitro, Wenbo Zhou, Chunmei Long, Anthony L. Fink, Vladimir N. Uversky
Calbindin-D28k Acts As A Calcium-Dependent Chaperone Suppressing Α-Synuclein Fibrillation In Vitro, Wenbo Zhou, Chunmei Long, Anthony L. Fink, Vladimir N. Uversky
Molecular Medicine Faculty Publications
α-Synuclein, a natively unfolded protein aggregation which is implicated in the pathogenesis of Parkinson’s disease and several other neurodegenerative diseases, is known to interact with a great number of unrelated proteins. Some of these proteins, such as ß-synuclein and DJ-1, were shown to inhibit α-synuclein aggregation in vitro and in vivo therefore acting as chaperones. Since calbindin-D28K is co-localized with Ca2+ neuronal membrane pumps, and since α-synuclein is also found in the membrane proximity, these two proteins can potentially interact in vivo. Here we show that calbindin-D28K interacts with α-synuclein and inhibits its fibrillation in a calcium-dependent manner, therefore potentially …