Session Time: 1:15pm-2:45pm
Location: Hall 3FG
Objective: In this study we aim to elucidate the role of Kif5b motor subunit in the nigrostriatal pathway. We have generated different conditional knockout mice for the Kif5b subunit of Kinesin-1 to unravel its contribution to locomotion.
Background: Locomotion is an intricate process controlled by the basal ganglia and regulated by fine-tuned dopaminergic innervations from neurons in the substantia nigra pars-compacta (SNpc). Dysfunctions in dopaminergic neurotransmission leads to movement initiation impairments, gaiting defects and hypolocomotion in a variety of collective diseases so called Parkinsonism. Due to its high polarity and extreme axonal arborization, neurons depend on molecular motor proteins and microtubule-based transport for their normal function. Intracellular transport defects have been associated with Parkinsonism since axonopathies, axonal clogging, microtubule destabilization and lower levels of motor proteins were described in patient brains. However, the contribution of specific molecular motors to the regulation of the nigrostriatal network remains unclear.
Methods: Conditional mutant mice lacking Kif5b from neurons or specifically from dopaminergic neurons were generated and evaluated using a battery of behavioral, pharmacological, neurochemical and cellular experiments.
Results: Mice with neuronal deletion of Kif5b showed hypolocomotion with movement initiation deficits and motor coordination impairments. High pressure liquid chromatography experiments determined that dopamine (DA) metabolism is impaired in neuronal Kif5b-KO; however, no dopaminergic cell loss was observed. Contrarily, deletion of Kif5b only in dopaminergic neurons is not sufficient to induce locomotor defects. Noteworthy, pharmacological stimulation of DA release together with agonist or antagonist of DA receptors revealed selective D2-dependent movement initiation defects in neuronal Kif5b-KO. Finally, subcellular fractionation from striatum, showed that Kif5b deletion reduced the amount of D2R in synaptic plasma membranes.
Conclusions: All this evidence strongly suggest the relevant contribution of Kif5b molecular motor subunit in the intracellular mechanisms necessary for nigrostriatal neuronal communication, which when impaired may lead to significant defects in motor coordination and overall locomotion. These results are important for understanding how molecular motor protein defects may contribute to the induction of locomotor impairments associated with parkinsonism.
To cite this abstract in AMA style:T. Falzone, L. Cromberg, M. Alloatti, I. Fernandez Bessone, T. Saez. Neuronal KIF5b deletion induces striatum-dependent locomotor impairments and defects in membrane presentation of dopamine D2 receptors [abstract]. Mov Disord. 2018; 33 (suppl 2). https://www.mdsabstracts.org/abstract/neuronal-kif5b-deletion-induces-striatum-dependent-locomotor-impairments-and-defects-in-membrane-presentation-of-dopamine-d2-receptors/. Accessed December 5, 2023.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/neuronal-kif5b-deletion-induces-striatum-dependent-locomotor-impairments-and-defects-in-membrane-presentation-of-dopamine-d2-receptors/