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Huntington's disease genotype suppresses global manganese-responsive processes in pre-manifest and manifest YAC128 mice

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Abstract

Manganese (Mn) is an essential micronutrient required for the proper function of several enzymes. Accumulating evidence demonstrates a selective decrease of bioavailable Mn in vulnerable cell types of Huntington's Disease (HD), an inherited progressive neurodegenerative disorder with no cure. Amelioration of underlying pathophysiology, such as alterations in Mn-dependent biology, may be therapeutic. We therefore sought to investigate global Mn-dependent and Mn-responsive biology following various Mn exposures in a mouse model of HD. YAC128 and wildtype (WT) littermate control mice received one of three different Mn exposure paradigms by subcutaneous injection of 50 mg kg−1 MnCl2·4(H2O) across two distinct HD disease stages. “Pre-manifest” (12-week old mice) mice received either a single (1 injection) or week-long (3 injections) exposure of Mn or vehicle (H2O) and were sacrificed at the pre-manifest stage. “Manifest” (32-week old) mice were sacrificed following either a week-long Mn or vehicle exposure during the manifest stage, or a 20-week-long chronic (2× weekly injections) exposure that began in the pre-manifest stage. Tissue Mn, mRNA, protein, and metabolites were measured in the striatum, the brain region most sensitive to neurodegeneration in HD. Across all Mn exposure paradigms, pre-manifest YAC128 mice exhibited a suppressed response to transcriptional and protein changes and manifest YAC128 mice showed a suppressed metabolic response, despite equivalent elevations in whole striatal Mn. We conclude that YAC128 mice respond differentially to Mn compared to WT as measured by global transcriptional, translational, and metabolomic changes, suggesting an impairment in Mn homeostasis across two different disease stages in YAC128 mice.

Graphical abstract: Huntington's disease genotype suppresses global manganese-responsive processes in pre-manifest and manifest YAC128 mice

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Supplementary files

Article information


Submitted
26 Mar 2020
Accepted
05 May 2020
First published
12 May 2020

Metallomics, 2020, Advance Article
Article type
Paper

Huntington's disease genotype suppresses global manganese-responsive processes in pre-manifest and manifest YAC128 mice

A. C. Pfalzer, J. M. Wilcox, S. G. Codreanu, M. Totten, T. J. V. Bichell, T. Halbesma, P. Umashanker, K. L. Yang, N. L. Parmalee, S. D. Sherrod, K. M. Erikson, F. E. Harrison, J. A. McLean, M. Aschner and A. B. Bowman, Metallomics, 2020, Advance Article , DOI: 10.1039/D0MT00081G

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