Saturday, May 17, 2025
5/17/2025
Mechanisms of nano plastic transport in the brain - Project Summary: Nanoplastics (plastic particles smaller than one micron) are ubiquitous in our environment. Nanoplastics are found in our food, drinking water, and even in the air we breathe. However, knowledge is just now emerging regarding the uptake and accumulation of nanoplastics into the body and how this may impact human health. Of particular concern is how nanoplastics may impact the brain. Exposure to airborne pollutants and toxins has been found to be a strong risk factor in the development of neurodegenerative disease, and interestingly, a decreased sense of smell (anosmia) has been found to be one of the best predictors of the development of neurodegenerative disease. This raises the possibility that nanoplastics can enter the brain via the olfactory system. The olfactory sensory neurons that line the nasal epithelium send direct axon projections into the brain, making the olfactory system a potential a conduit for inhaled foreign substances to enter the brain. In neurons, the active transport of vesicles and organelles down axons from the neuronal cell body to synapses is carried out by kinesin motor proteins that walk along microtubule tracks. The overarching hypothesis of the proposed work is that nanoplastics are taken up by neurons in the periphery, hijack the kinesin-microtubule axonal transport machinery, and are thereby rapidly transported into the brain. To test this model, we (neuroscientist Drew and biophysicist Hancock) will investigate plastic nanoparticle uptake in the mouse olfactory system in vivo and nanoparticle interactions with kinesin motor proteins in vitro. Our preliminary studies have shown that intranasal application of fluorescent polystyrene nanoparticles in mice results in nanoparticle uptake by olfactory sensory neurons and spreading to the olfactory bulb over just a few hours. This transport is far too rapid to be accounted for by diffusion, suggesting the possibility that the nanoparticles are actively transported by kinesins. It is known that kinesins can bind to plastic nanoparticles through their tail domain, which normally binds intracellular cargo. Using nanoplastics of different size, shape, and surface chemistry, we will use single-molecule microscopy experiments to investigate the rules governing the binding of kinesin-1, 2 and 3 family transport motors to plastic nanoparticles, and their resulting transport along microtubules. We hypothesize that the kinesin tail domain is inherently ‘sticky,’ and that binding to nanoparticle surfaces relieves the normal autoinhibition of these motors, which normally prevents their mislocalization in the absence of cargo. In parallel, we will use histology and in vivo microscopy to investigate the dynamics and the potential pathways that nanoparticles may use to enter the brain. These combined in vivo and in vitro experiments will provide a comprehensive understanding of nanoplastics uptake and transport in the olfactory system, and will test the important potential link between nanoplastics exposure and neurological disease.
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