Deciphering the Physiological Roles of KIF2A in Mature Neurons and the Relation Between KIF2A-Downregulation and Neurodegeneration

Details

Supervisors

Tissir, Fadel

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

Background: Neurodevelopmental disorders and neurodegeneration, initially perceived as distinct, now reveal surprising similarities through shared molecular and genomic characteristics, notably involving microtubules (MTs). These key components of the cytoskeleton play crucial roles in neuronal cells, and alterations in their dynamics are associated with the aforementioned disorders. Posttranslational modifications of tubulin and microtubule-associated proteins, including kinesin-like protein 2a (Kif2a), regulate the dynamic process of MTs. The binding of Kif2a to MTs allows for their depolymerisation, thus managing the overall dynamics of these polymers. Kif2a is therefore involved in numerous MT-dependent processes during brain development, such as proliferation, migration, polarisation, as well as neuronal morphology and connectivity. In mice, Kif2a deletion leads to the over-stabilisation of MTs in neurons, resulting in abnormalities in neural development and postnatal neurodegeneration. Kif2a is also expressed in mature neurons; however, its precise role in the latter is still to be elucidated. Moreover, recent studies suggest that rare variants and differences in KIF2A expression may be involved in Alzheimer’s disease (AD). The brains of individuals with AD show decreased MT dynamics, leading to an elevation in stable MT linked to synaptic dysfunction and cognitive deterioration. On the other hand, stabilising MTs results in increased Tau phosphorylation and Tau-dependent loss of dendrites. However, the specific impact of MT dysregulation on Tau phosphorylation and the progression of the disease remains unclear. Objectives: The objectives of the present study are therefore 1) to understand the physiological and pathological roles of Kif2a in mature neurons in mice, and 2) to investigate the expression of KIF2A in AD human patients.