Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Public Health

First Advisor's Name

Tomas R. Guilarte

First Advisor's Committee Title

Co-Committee Chair

Second Advisor's Name

Kim Tieu

Second Advisor's Committee Title

Co-Committee Chair

Third Advisor's Name

Jason R. Richardson

Third Advisor's Committee Title

Committee Member

Fourth Advisor's Name

Timothy A. Allen

Fourth Advisor's Committee Title

Committee Member

Keywords

Manganese, SLC39A14, manganism, dystonia, parkinsonism, cerebellum, parkinson's

Date of Defense

3-27-2023

Abstract

Over the last decade, clinical reports have outlined cases of childhood-onset manganese (Mn)-induced dystonia-parkinsonism, resulting from loss-of-function mutations in the Mn influx transporter gene SLC39A14. The affected individuals present with a complex motor phenotype of early-onset Mn-induced dystonia-parkinsonism. Currently there is a paucity of knowledge regarding the underlying neuropathophysiology and potential therapeutic approaches. However, these clinical cases provided a wealth of information on Mn neurotoxicity and homeostasis. The recently available Slc39a14-knockout (KO) murine model provides a powerful tool to investigate the neurological effects and molecular and cellular mechanisms of elevated blood and brain Mn concentrations in vivo.

To that end, this body of work is focused on a detailed characterization of the Slc39a14-KO murine model from neurobehavioral, neurochemical, and neuroanatomical perspectives. We discovered that 60-day old Slc39a14-KO male and female mice accumulate blood and brain Mn at levels representative of those measured in the human disease. Furthermore, the KO mice develop motor deficits and movement abnormalities consistent with the deficits seen in humans. In the context of elevated blood and brain Mn concentrations and dystonia-like motor phenotype, we have discovered that the key region of the brain that is typically associated with neurodegeneration in parkinsonism movement disorders including Parkinson’s Disease – the Substantia Nigra pars compacta (SNpc)does not exhibit neurodegeneration as measured by tyrosine-hydroxylase positive neuron number, dopaminergic terminals integrity, or dopamine levels. Yet, while no evidence of neurodegeneration of dopaminergic neurons in the SNpc was observed, the SNpc dopaminergic neurons were found to be markedly compromised in their ability to release dopamine under KCl stimulated conditions. These findings were further confirmed using a life course approach in ageing 365-day old Slc39a14-KO animals. Furthermore, to our knowledge, this is the first report to outline neurodegenerative changes in the cerebellum and brain stem of Slc39a14-KO mice in the context of elevated cerebellar Mn levels. We interrogated changes in the hindbrain of Slc39a14-KO mice by assessing neuroinflammatory and cytoarchitectural changes throughout the brain. Our preliminary studies also indicate for the first time putative neurodegenerative changes in cellular populations of the cerebellum and brainstem, brain regions that play a critical role in gait, posture, movement, and balance. Collectively, the Slc39a14-KO murine model provides a novel approach to investigate the human disease and expand our overall knowledge of Mn neurotoxicity.

Identifier

FIDC011076

ORCID

00000-0003-1896-8485

Previously Published In

Rodichkin, A. N., and Guilarte, T. R. (2022) Hereditary Disorders of Manganese Metabolism: Pathophysiology of Childhood-Onset Dystonia-Parkinsonism in SLC39A14 Mutation Carriers and Genetic Animal Models. Int J Mol Sci 23

Rodichkin, A.N., Edler, M.K., McGlothan, J.L., Guilarte, T.R., (2021) Behavioral and neurochemical studies of inherited manganese-induced dystonia-parkinsonism in Slc39a14-knockout mice. Neurobiol. Dis. 158, 105467.

Rodichkin, A. N., Edler, M. K., McGlothan, J. L., and Guilarte, T. R. (2022) Pathophysiological studies of aging Slc39a14 knockout mice to assess the progression of manganese-induced dystonia-parkinsonism. Neurotoxicology 93, 92-102

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