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

Metallomics - Tập 12 Số 7 - Trang 1118-1130 - 2020
Anna C. Pfalzer1, Jordyn M. Wilcox1,2,3, Simona G. Codreanu4,5, Melissa S. Totten6, Terry Jo Bichell1, Timothy C. Halbesma1, Preethi Umashanker1, Kevin Yang1, Nancy L. Parmalee7, Stacy D. Sherrod4,5, Keith M. Erikson6, Fiona E. Harrison8,2,3, John A. McLean4,5, Michael Aschner7, Aaron B. Bowman9,2
1Department of Neurology; Vanderbilt University Medical Center; Nashville, TN USA.
2Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA
3Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University Medical Center, Nashville, TN, USA
4Center for Innovative Technology, Vanderbilt University, Nashville, TN, USA
5Department of Chemistry, Vanderbilt University, Nashville, TN, USA
6Department of Nutrition, University of North Carolina-Greensboro, Greensboro, NC, USA
7Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
8Department of Medicine, Vanderbilt University Medical Center, Nashville, TN USA.
9School of Health Sciences, Purdue University, 550 Stadium Mall Drive – HAMP 1173A, West Lafayette, IN 47907-2051, USA. Tel: +1 765-494-2684

Tóm tắt

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.

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Metallomics

Tập 12 Số 7

1118-1130

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