The misfolding mystery: α-synuclein and the pathogenesis of Parkinson's disease.

Neurodegenerative diseases such as Parkinson's disease (PD) are characterized by the death of neurons in specific areas of the brain. One of the proteins that is involved in the pathogenesis of PD is α-synuclein (α-syn). α-Syn is a normal protein that is found in all neurons, but in PD, it misfolds and aggregates into toxic fibrils. These fibrils can then coalesce into pathological inclusions, such as Lewy bodies and Lewy neurites. The pathogenic pathway of PD is thought to involve a number of steps, including misfolding and aggregation of α-syn, mitochondrial dysfunction, protein clearance impairment, neuroinflammation and oxidative stress. A deeper insight into the structure of α-syn and its fibrils could aid in understanding the disease's etiology. The prion-like nature of α-syn is also an important area of research. Prions are misfolded proteins that can spread from cell to cell, causing other proteins to misfold as well. It is possible that α-syn may behave in a similar way, spreading from cell to cell and causing a cascade of misfolding and aggregation. Various post-translational alterations have also been observed to play a role in the pathogenesis of PD. These alterations can involve a variety of nuclear and extranuclear activities, and they can lead to the misfolding and aggregation of α-syn. A better understanding of the pathogenic pathway of PD could lead to the development of new therapies for the treatment of this disease.

Negi S ，Khurana N ，Duggal N 《-》

α-Synuclein misfolding and aggregation: Implications in Parkinson's disease pathogenesis.

α-Synuclein (α-Syn) has been extensively studied for its structural and biophysical properties owing to its pathophysiological role in Parkinson's disease (PD). Lewy bodies and Lewy neurites are the pathological hallmarks of PD and contain α-Syn aggregates as their major component. It was therefore hypothesized that α-Syn aggregation is actively associated with PD pathogenesis. The central role of α-Syn aggregation in PD is further supported by the identification of point mutations in α-Syn protein associated with rare familial forms of PD. However, the correlation between aggregation propensities of α-Syn mutants and their association with PD phenotype is not straightforward. Recent evidence suggested that oligomers, formed during the initial stages of aggregation, are the potent neurotoxic species causing cell death in PD. However, the heterogeneous and unstable nature of these oligomers limit their detailed characterization. α-Syn fibrils, on the contrary, are shown to be the infectious agents and propagate in a prion-like manner. Although α-Syn is an intrinsically disordered protein, it exhibits remarkable conformational plasticity by adopting a range of structural conformations under different environmental conditions. In this review, we focus on the structural and functional aspects of α-Syn and role of potential factors that may contribute to the underlying mechanism of synucleinopathies. This information will help to identify novel targets and develop specific therapeutic strategies to combat Parkinson's and other protein aggregation related neurodegenerative diseases.

Mehra S ，Sahay S ，Maji SK 《-》

Applying chaperones to protein-misfolding disorders: molecular chaperones against α-synuclein in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of a protein called α-synuclein (α-syn) into inclusions known as lewy bodies (LB) within neurons. This accumulation is also due to insufficient formation and activity of dopamine produced in certain neurons within the substantia nigra. Lewy bodies are the pathological hallmark of the idiopathic disorder and the cascade that allows α-synuclein to misfold, aggregate and form these inclusions has been the subject of intensive research. Targeting these early steps of oligomerization is one of the main therapeutic approaches in order to develop neurodegenerative-modifying agents. Because the folding and refolding of alpha synuclein is the key point of this cascade, we are interested in this review to summarize the role of some molecular chaperones proteins such as Hsp70, Hsp90 and small heat shock proteins (sHsp) and Hsp 104. Hsp70 and its co-chaperone, Hsp70 and small heat shock proteins can prevent neurodegeneration by preventing α-syn misfolding, oligomerization and aggregation in vitro and in Parkinson disease animal models. Hsp104 is able to resolve disordered protein aggregates and cross beta amyloid conformers. Together, these chaperones have a complementary effect and can be a target for therapeutic intervention in PD.

Chaari A ，Hoarau-Véchot J ，Ladjimi M 《-》

Methods for detecting toxic α-synuclein species as a biomarker for Parkinson's disease.

O'Hara DM ，Kalia SK ，Kalia LV 《-》

Synapsin III is a key component of α-synuclein fibrils in Lewy bodies of PD brains.

Longhena F ，Faustini G ，Varanita T ，Zaltieri M ，Porrini V ，Tessari I ，Poliani PL ，Missale C ，Borroni B ，Padovani A ，Bubacco L ，Pizzi M ，Spano P ，Bellucci A ... -  《-》