GM1 oligosaccharide efficacy against α-synuclein aggregation and toxicity in vitro.

Fibrillary aggregated α-synuclein represents the neurologic hallmark of Parkinson's disease and is considered to play a causative role in the disease. Although the causes leading to α-synuclein aggregation are not clear, the GM1 ganglioside interaction is recognized to prevent this process. How GM1 exerts these functions is not completely clear, although a primary role of its soluble oligosaccharide (GM1-OS) is emerging.

Non-SUMOylated alternative spliced isoforms of alpha-synuclein are more aggregation-prone and toxic.

The exon skipping of α-Synuclein (α-Syn), the main constituent of the abnormal protein aggregation in Lewy bodies of Parkinson's disease (PD), forms four isoforms. In contrast to the full length α-Syn (α-Syn 140), little is known about the splice isoforms' properties and functions. SUMOylation, a post-translational modification, regulates α-Syn function, aggregation, and degradation, but information about α-Syn isoforms and the effect of SUMOylation on them is unknown.

Brain region-specific susceptibility of Lewy body pathology in synucleinopathies is governed by α-synuclein conformations.

The protein α-synuclein, a key player in Parkinson's disease (PD) and other synucleinopathies, exists in different physiological conformations: cytosolic unfolded aggregation-prone monomers and helical aggregation-resistant multimers. It has been shown that familial PD-associated missense mutations within the α-synuclein gene destabilize the conformer equilibrium of physiologic α-synuclein in favor of unfolded monomers. Here, we characterized the relative levels of unfolded and helical forms of cytosolic α-synuclein in post-mortem human brain tissue and showed that the equilibrium of α-synuclein conformations is destabilized in sporadic PD and DLB patients.

In silico/in vitro screening and hit evaluation identified new phenothiazine anti-prion derivatives.

Prion diseases or transmissible spongiform encephalopathies (TSEs) are a group of rare neurodegenerative disorders. TSEs are characterized by the accumulation of prions (PrP) that represent pathological isoforms of the physiological cellular prion protein PrP. Although the conversion of PrP to PrP is still not completely understood, blocking this process may lead to develop new therapies.

Analysis of α-synuclein species enriched from cerebral cortex of humans with sporadic dementia with Lewy bodies.

Since researchers identified α-synuclein as the principal component of Lewy bodies and Lewy neurites, studies have suggested that it plays a causative role in the pathogenesis of dementia with Lewy bodies and other 'synucleinopathies'. While α-synuclein dyshomeostasis likely contributes to the neurodegeneration associated with the synucleinopathies, few direct biochemical analyses of α-synuclein from diseased human brain tissue currently exist. In this study, we analysed sequential protein extracts from a substantial number of patients with neuropathological diagnoses of dementia with Lewy bodies and corresponding controls, detecting a shift of cytosolic and membrane-bound physiological α-synuclein to highly aggregated forms.

Identification of novel fluorescent probes preventing PrP replication in prion diseases.

Prion diseases are serious, not curable neurodegenerative disorders caused by the accumulation of the misfolded protein PrP that represents the pathological variant of the normally folded cellular protein PrP. Molecules that bind the cellular isoform PrP preventing its misfolding, could arrest the progression of pathological conditions related to the abnormal PrP protein. In this context, by combining 3D-QSAR model, derived from pharmacophore-based alignment, with molecular docking procedures and physico-chemical properties prediction we have developed a virtual screening protocol to find novel chemicals able to prevent PrP misfolding.