Intracellular Mechanisms of α-Synuclein Processing

The aggregation of α-synuclein is the pathological hallmark of a group of neurological disorders collectively known as synucleinopathies. These include Parkinson’s disease, dementia with Lewy Bodies, multiple systems atrophy and some forms of neurodegeneration with brain iron accumulation. While these neurodegenerative disorders present with distinctive clinical features, they all converge in one thing: α-synuclein aggregates. Despite the central role of α-synuclein in all these disorders, little is known about the mechanisms that lead to its aggregation. Recent studies indicate aggregation of the protein in the cytosol as well as within lysosomes, where most of α-synuclein degradation takes place. Moreover, intracellular α-synuclein aggregates have been shown to interfere with normal cell function. These essential cellular functions include: disruptions in the secretory and endocytic trafficking pathways, mitochondrial as well as lysosomal function and calcium homeostasis all leading to disease pathology.

This Research Topic seeks to understand the mechanisms that lead to intracellular α-synuclein aggregation and the cellular pathways it affects. Although there is a clear pathological link between α-synuclein aggregates and disease pathology, the molecular mechanisms that lead to intracellular α-synuclein aggregation are not well understood. It would be important to gain more information about structural characteristics of α-synuclein aggregation that confer cell specificity, if any. We also seek to highlight recent studies focusing on the interference of pathological α-synuclein conformers with normal cell function. Another aspect which we would like to emphasize in this Research Topic, is the degradation of α-synuclein by either proteasomal or lysosomal pathways. Since decreasing intracellular protein levels of α-synuclein could be a potential therapeutic target, it is important to understand the molecular details of these protein degradation pathways.

In summary, this Research Topic is focused on gaining a better understanding of the intracellular mechanisms that mediate α-synuclein homeostasis that ultimately lead to disease pathology, which will enable us to design better therapeutic strategies in the future. We welcome submissions covering the following topics:

● intracellular α-synuclein aggregation
● α-synuclein degradation pathways (lysosomal, proteasomal)
● intracellular α-synuclein toxicity
● intracellular effects of α-synuclein on cell function
● structural details of intracellular α-synuclein conformers
● therapeutic strategies lowering intracellular α-synuclein protein level
● posttranslational modifications on α-synuclein
● α-synuclein-based diagnostics for neurological disorders