Neuronal KIF5b deletion induces striatum‐dependent locomotor impairments and defects in membrane presentation of dopamine D2 receptors

Abstract

The process of locomotion is controlled by fine-tuned dopaminergic neurons in the Substantia Nigra pars-compacta (SNpc) that projects their axons to the dorsal striatum regulating cortical innervations of medium spiny neurons. Dysfunction in dopaminergic neurotransmission within the striatum leads to movement impairments, gaiting defects, and hypo-locomotion. Due to their high polarity and extreme axonal arborization, neurons depend on molecular motor proteins and microtubule-based transport for their normal function. Transport defects have been associated with neurodegeneration since axonopathies, axonal clogging, microtubule destabilization, and lower motor proteins levels were described in the brain of patients with Parkinson's Disease and other neurodegenerative disorders. However, the contribution of specific motor proteins to the regulation of the nigrostriatal network remains unclear. Here, we generated different conditional knockout mice for the kinesin heavy chain 5B subunit (Kif5b) of Kinesin-1 to unravel its contribution to locomotion. Interestingly, mice with neuronal Kif5b deletion showed hypo-locomotion, movement initiation deficits, and coordination impairments. High pressure liquid chromatography determined that dopamine (DA) metabolism is impaired in neuronal Kif5b-KO, while no dopaminergic cell loss was observed. However, the 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 dopamine D2 receptor in synaptic plasma membranes. Together, these results revealed an important role for Kif5b in the modulation of the striatal network that is relevant to the overall locomotor response. Abbreviations used: APP, amyloid precursor protein; D1R, dopamine receptor D1; D2R, dopamine receptor D2; DA, dopamine; DAK5b-KO, Kif5b loxP/loxP ;Dat +/ires-cre mice; DArgic, dopaminergic; HPLC, high pressure liquid chromatography; KHC, kinesin heavy chain; Kif5b, kinesin heavy chain 5B subunit; MAO, monoamine oxidase; MSN, medium spiny neurons; NeuK5b-KO, Kif5b loxP/loxP ;Tg.(Nes-cre) mice; PD, Parkinson disease; RRID, research resource identifier (see scicrunch.org); SNpc, substantia nigra pars compacta. 362

Urinary exosomal microRNAs as predictive biomarkers for persistent psychotic-like experiences

“…hsa-miR-142-3p and hsa-miR-199a-3p identified in the present study have been experimentally shown to regulate KIF5B 55,56 . KIF5B is a motor protein in the dopaminergic synapse pathway and a member of the kinesin superfamily (KIF) 57,58 . KIF5B working with DISC1 is associated with the axonal transport of synaptic cargoes 59 and is involved in neuron dopamine metabolism 58 .…”

“…KIF5B is a motor protein in the dopaminergic synapse pathway and a member of the kinesin superfamily (KIF) 57,58 . KIF5B working with DISC1 is associated with the axonal transport of synaptic cargoes 59 and is involved in neuron dopamine metabolism 58 . Some studies suggest that dopamine dysregulation is a mechanism underlying PLE 60,61 .…”

Exogenous L-lactate administration in rat hippocampus increases expression of key regulators of mitochondrial biogenesis and antioxidant defense

“…Another interesting finding from the proteomics study was the increased expression of KIF5B in the hippocampus of L-lactate-treated rats. KIF5B is the main kinesin motor driving anterograde mitochondrial axonal transport in neuron ( Lackner, 2014 ; Cromberg et al, 2019 ). Previous studies showed that KIF5B is crucial for dendritic spine morphogenesis, synaptic plasticity, and memory formation ( Cai et al, 2007 ; Zhao et al, 2020 ).…”

Microtubule acetylation dyshomeostasis in Parkinson’s disease

“…Although not furnished in this particular study, the impairment of KIF5-mediated neuronal transport would most likely also affect mitochondrial trafficking, as these are the motor proteins involved in the axonal anterograde transport of mitochondria, as indicated by other studies. Impairment in KIF5-mediated axonal transport has also been directly linked with striatal dopaminergic neuronal loss [ 118 , 119 ]. Embryonic primary neuron cultures lacking the CCP1 gene showed immense tubulin hyperglutamylation, and the time expenditure of anterograde and retrograde mitochondrial movement was reduced by 50% without any compromise in the run length or speed of transport [ 120 , 121 ].…”