Frontiers Journal of Neurology & Neuroscience

Parkinson's Disease Associated With Traumatic Brain Injury: An Alpha-synuclein-mediated Chronic Disseminated Brain Inflammation

Abstract

Substantial evidence shows that traumatic brain injury (TBI) can increase the risk of Parkinson’s disease (PD), but the mechanism has remained unclear. It has been reported that TBI can induce the accumulation of alpha-synuclein (?-Syn). The mechanisms of protein accumulation after TBI might include: 1. Impaired axonal transport. 2. Malfunction of the ubiquitin (Ub)-proteasome system, chaperone mediated autophagy and macroautophagy. 3. Impairment of glymphatic pathway. 4. The extracellular ATP. 5. The oxidative and nitrative stress. In summary, TBI can cause both brain inflammation, and the accumulation of ?-Syn. Animal model studies have shown that brain inflammation through injection of lipopolysaccharides can cause the overexpression and accumulation of ?-Syn; in turn the accumulation of ?-Syn through intracerebral injection of recombinant ?-Syn can cause brain inflammation. Recently both clinical and animal studies have found that brain inflammation after TBI is not only limited to the local brain injury site, but can also spread to the distal region of the brain. Moreover, an animal study found that intracerebral injection of amyloidogenic ?-Syn could induce the spread of the ?-Syn proteinopathy to brain regions distal from the injection site. Therefore, based on the above evidences, we propose that TBI-induced PD is ?-Syn-mediated chronic disseminated brain inflammation mechanism. In this pathological process, the local accumulation of ?-Syn induces microglial activation in the surrounding brain tissue. The local chronic brain inflammation can continually cause the accumulation of ?-Syn. Both brain inflammation and accumulation of ?-Syn can trigger neuronal apoptosis. Such a vicious cycle gradually disseminates the ?-Syn and inflammation from the local TBI area to the substantia nigra. We believe this disseminated pathological response is depended on the genetic and environmental conditions. Thus, studying the genetic and environmental factors as well as the activation of microglia can assist in the prevention and treatment of such conditions.

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