Electronic Thesis and Dissertation Repository

Thesis Format



Master of Science




Prado, Marco

2nd Supervisor

Prado, Vania

Joint Supervisor


A common hallmark of neurodegenerative diseases is the formation and spreading of misfolded protein. In synucleinopathies, the aggregation-prone alpha-synuclein (α-syn) is the pivotal player. At present, whether cognitive deficits in synucleinopathies arise due to increased protein misfolding is unclear. We utilized the Bussey-Saksida touchscreen system to study the impact of α-syn pathology on cognition. M83 homozygous mice, a model of synucleinopathy, were impaired in reversal learning in the Pairwise Visual Discrimination (PVD) reversal task, but do not show attentional impairments in the 5-Choice Serial Reaction Time task. In contrast, M83 hemizygous mice do not show deficits in the PVD reversal task. Moreover, when α-syn pathology was accelerated using α-syn preformed fibrils in M83 hemizygous mice, impairments were induced early in the PVD reversal task in conjunction with wide distribution of α-syn aggregates in the brain. Together, our findings indicate that accumulation and spreading of α-syn triggers cognitive deficits in M83 mice, specifically in behavioural flexibility.

Summary for Lay Audience

A key feature of neurodegenerative diseases is the misfolding and aggregation of proteins. Alpha synuclein (α-syn) is predominantly misfolded in a group of disorders termed synucleinopathies, which include Parkinson’s Disease and Lewy Body with Dementia. Previously, α-syn aggregation and spreading have been associated with motor symptoms in synucleinopathies, but the question remains whether it also causes cognitive deficits. In this study, we aimed to assess the cognitive function of a mouse model of synucleinopathy (M83) which carries the A53T human mutant α-syn and determine the effect of α-syn spreading on cognition in M83 mice. Noteworthy, the cognitive function of M83 mouse model has not been largely assessed. To evaluate cognitive function in M83 mice, we used the Bussey-Saksida touchscreen system which incorporates multiple tasks (similar to those used in humans) for assessment of high-level cognitive function in rodents. We observed that M83 mice were impaired in cognitive flexibility but not in attention, suggesting that the A53T α-syn mutation can cause cognitive flexibility deficits. Furthermore, we also observed that propagation of α-syn in the brain of M83 mice led to impairments in cognitive flexibility. Together, these data suggest that α-syn spreading triggers cognitive deficits in synucleinopathies.