Abstract
Aggregation of alpha-synuclein (ASYN) in Lewy bodies and Lewy neurites is the typical pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Furthermore, mutations in the gene encoding for ASYN are associated with familial and sporadic forms of PD, suggesting this protein plays a central role in the disease. However, the precise contribution of ASYN to neuronal dysfunction and death is unclear. There is intense debate about the nature of the toxic species of ASYN and little is known about the molecular determinants of oligomerization and aggregation of ASYN in the cell. In order to clarify the effects of different mutations on the propensity of ASYN to oligomerize and aggregate, we assembled a panel of 19 ASYN variants and compared their behaviour. We found that familial mutants linked to PD (A30P, E46K, H50Q, G51D and A53T) exhibited identical propensities to oligomerize in living cells, but had distinct abilities to form inclusions. While the A30P mutant reduced the percentage of cells with inclusions, the E46K mutant had the opposite effect. Interestingly, artificial proline mutants designed to interfere with the helical structure of the N-terminal domain, showed increased propensity to form oligomeric species rather than inclusions. Moreover, lysine substitution mutants increased oligomerization and altered the pattern of aggregation. Altogether, our data shed light into the molecular effects of ASYN mutations in a cellular context, and established a common ground for the study of genetic and pharmacological modulators of the aggregation process, opening new perspectives for therapeutic intervention in PD and other synucleinopathies.
Highlights
Alpha-synuclein (ASYN) is an abundant neuronal protein whose normal function is still elusive, but seems to be related to SNAREcomplex assembly [1]
In Parkinson’s disease (PD), the protein alpha-synuclein (ASYN) is the major component of aggregates known as Lewy bodies
The present hypothesis is that smaller aggregated species, known as oligomers, might constitute the toxic forms of ASYN
Summary
Alpha-synuclein (ASYN) is an abundant neuronal protein whose normal function is still elusive, but seems to be related to SNAREcomplex assembly [1]. Misfolding and aggregation of ASYN in proteinaceous inclusions, known as Lewy bodies (LBs), are associated with Parkinson’s disease (PD) and other neurodegenerative disorders known as synucleinopathies [2,3]. PD is the second most common neurodegenerative disease, affecting approximately 1% of the population over 65 years of age [4], and is a growing problem in the aging population. Both point mutations [5,6,7] and multiplications [8,9,10,11] of the SNCA gene, encoding for ASYN, have been linked to autosomaldominant forms of PD. The G51D mutation is associated with early onset of disease [15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
