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STUDY OF THE PATHOLOGICAL EFFECT OF THE NOVEL <EM>RS199645736G>A</EM> MUTATION IN THE HUMAN SYN3 GENE
Francesco Amodeoand 6 co-authors
University of Brescia
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS03-08AM-076
Presentation
Date TBA
Board: PS03-08AM-076
Event Information
Poster Board
PS03-08AM-076
Poster
View posterAbstract
Parkinson’s Disease (PD) is characterized by nigrostriatal dopaminergic neuron loss and accumulation of fibrillary aggregated α-synuclein (α-syn) in Lewy bodies (LB). Recently, synapsin III (syn III) has emerged as a new key α-syn interactant modulating the fibrillary aggregation of α-syn and it has been also found to participate in α-syn pathology in PD and dementia with LB (DLB). In addition, network proteomic studies support that Syn III increase serve as discriminant factor between PD with dementia or DLB and Alzheimer’s disease. Our team has recently identified a novel mutation of the human SYN3 gene (rs199645736G>A) in a patient suffering from an early onset parkinsonism. In order to gain insights into the possible pathogenic role of this novel mutation, we expressed rs199645736G>A mutant and wild type (wt) Syn III in SK-N-SH neuroblastoma cells in basal condition or subjected to dopaminergic-like differentiation. We observed that the rs199645736G>A mutation altered the physiological expression of other synapsin isoforms and induced a reduction in total α-syn protein levels. Moreover, cells expressing mutant Syn III showed an altered morphology characterized by a reduction in soma area and number of processes compared to cells expressing wt syn III. Finally, cells expressing mutant syn III displayed an increase in p62 expression and aggregation supportive of autophagy engulfment. These findings indicate that the rs199645736G>A mutation impairs physiological functions of syn III affecting neuronal homeostasis, maturation and autophagy, suggesting that it may induce Parkinson-like pathology through different mechanisms than wt syn III.
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