Duncan NRI Faculty and Staff Publications
Language
English
Publication Date
9-22-2025
Journal
Neurobiology of Disease
DOI
10.1016/j.nbd.2025.107115
PMID
40992700
Abstract
Humans with pathogenic variants of the manganese (Mn) transporter gene SLC39A14 exhibit highly elevated brain Mn concentrations and childhood-onset dystonia-parkinsonism. Here we show that Slc39a14-knockout (KO) mice, a preclinical model of the disease with elevated Mn concentrations in the CB, express deficits in physiological tremor implicating cerebellar (CB) dysfunction. Imaging of intracellular Mn in Purkinje cells (PCs) using synchrotron-based X-ray fluorescence microscopy confirmed highly elevated Mn concentrations in the PCs of Slc39a14-KO mice. To determine biological pathways altered in the CB of Slc39a14-KO mice relative to wildtype (WT), we performed RNA sequencing and discovered significant upregulation of pathways and genes regulating immune response and cell death. To substantiate these findings, we performed quantitative autoradiography of the neuroinflammation biomarker Translocator Protein 18 kDa (TSPO) which was significantly increased in the CB of Slc39a14-KO mice relative to WT. The latter findings were confirmed via immunostaining with the microglial marker Iba-1, revealing widespread microglia activation and clustering in the CB cortex. Immunostaining for cleaved caspase-3 (cCASP3), a marker of apoptosis, showed increased number of PCs with positive immunolabeling for cCASP3 in Slc39a14-KO mice relative to WT. Degeneration of PCs was confirmed by Hematoxylin and Eosin (H&E) staining. Lastly, functional electrophysiological assessment of CB neurocircuitry revealed a marked decrease in firing rates of cerebellar nuclei (CN) neurons and increased variability of PC simple spikes firing. Collectively, these findings show, for the first time, Mn-induced PC degeneration and dysfunctional CB circuitry in Slc39a14-KO mice providing additional evidence for the pathological underpinnings of the dystonia-like movements, balance, and gait abnormalities in SLC39A14 mutation carriers.
Keywords
Cerebellum, Dystonia, Manganese, Manganese-induced dystonia-parkinsonism, Manganism, Neurodegeneration, Purkinje cells, SLC39A14
Published Open-Access
yes
Recommended Citation
Rodichkin, Alexander N; Brown, Amanda M; Devabathini, Pavani; et al., "Cerebellar Dysfunction in a Mouse Model of Childhood-Onset Manganese-Induced Dystonia Parkinsonism" (2025). Duncan NRI Faculty and Staff Publications. 179.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/179
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Genetic Phenomena Commons, Medical Genetics Commons, Neurology Commons, Neurosciences Commons