Transport of alpha-synuclein across the blood-cerebrospinal fluid barrier and effects of manganese exposure
Parkinson's disease is a member of a family of neurodegenerative disorders referred to as parkinsonism, which is characterized by the symptoms dyskinesia, tremors, and postural instability. A hallmark of multiple parkinsonian disorders is the presence of toxic, inclusions in surviving neurons known as Lewy bodies that are resistant to degradation and primarily comprised of highly organized fibrils of the protein, α-synuclein (a-Syn). These and other aggregated a-Syn species can be ejected the interstitial fluid, which merges seamlessly with the cerebrospinal fluid (CSF). The CSF is produced and regulated from within the choroid plexus by the blood-cerebrospinal fluid barrier (BCB), which is essential for the removal of waste products from the CSF and brain homeostasis. Despite extensive research on the association of a-Syn levels in the CSF with parkinsonian diagnosis, the regulation of a-Syn in the CSF by the BCB remains poorly understood. Multiple parkinsonian pathologies strongly implicate the exposure to various external factors such as the heavy metal manganese (Mn). Mn exposure has been implicated specifically in PD pathoetiology via direct, intermolecular interactions that promote a-Syn aggregation. Additionally, Mn has been shown to accumulate in the BCB following Mn exposure and induce the dyshomeostasis of copper (Cu), another essential trace heavy metal implicated in a-Syn dysfunction and parkinsonism. These findings allude to potential toxic interactions between a-Syn and Mn or Cu at the BCB that could contribute to the progression of parkinsonism. The research discussed in this dissertation was designed to test the central hypotheses that 1) the BCB plays an integral role in cleansing a-Syn from the CSF and 2) Mn exposure alters the uptake, clearance of a-Syn by the BCB, which will ultimately contribute to a-Syn-associated neuronal injury and parkinsonism. The studies from this project clearly indicated that 1) Mn and Cu exposures induced the accumulation of a-Syn expressed by the BCB; 2) The aggregation of a-Syn at the BCB was altered by direct, intermolecular interactions between Mn and a-Syn or Cu and a-Syn; 3) The BCB transported a-Syn in both directions in vitro and was unaffected by Mn exposure; 4) Mn exposure may have altered a-Syn clearance from the CSF by the CP in a rat model. Overall, we conclude that Mn exposure at the BCB may induce minor a-Syn dysfunction at the BCB but does not significantly affect the regulation of a-Syn by the BCB. Consequently, Mn exposure at the BCB specifically does not significantly contribute to parkinsonism.
Zheng, Purdue University.
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