Research Paper Volume 12, Issue 14 pp 15134—15156

Signatures of cell stress and altered bioenergetics in skin fibroblasts from patients with multiple sclerosis

Jordan M. Wilkins1, *, , Oleksandr Gakh1, *, , Parijat Kabiraj1, , Christina B. McCarthy1, , W. Oliver Tobin1, , Charles L. Howe1,2,3, , Claudia F. Lucchinetti1, ,

  • 1 Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
  • 2 Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
  • 3 Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN 55905, USA
* Equal contribution

Received: April 1, 2020       Accepted: June 5, 2020       Published: July 8, 2020      

https://doi.org/10.18632/aging.103612
How to Cite
This article has been corrected. See Correction. Aging (Albany NY). 2021; 13:7707-7707 . https://doi.org/10.18632/aging.202757  PMID: 33657013

Copyright: © 2020 Wilkins et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Multiple sclerosis (MS) is a central nervous system inflammatory demyelinating disease and the most common cause of non-traumatic disability in young adults. Despite progress in the treatment of the active relapsing disease, therapeutic options targeting irreversible progressive decline remain limited. Studies using skin fibroblasts derived from patients with neurodegenerative disorders demonstrate that cell stress pathways and bioenergetics are altered when compared to healthy individuals. However, findings in MS skin fibroblasts are limited. Here, we collected skin fibroblasts from 24 healthy control individuals, 30 patients with MS, and ten with amyotrophic lateral sclerosis (ALS) to investigate altered cell stress profiles. We observed endoplasmic reticulum swelling in MS skin fibroblasts, and increased gene expression of cell stress markers including BIP, ATF4, CHOP, GRP94, P53, and P21. When challenged against hydrogen peroxide, MS skin fibroblasts had reduced resiliency compared to ALS and controls. Mitochondrial and glycolytic functions were perturbed in MS skin fibroblasts while exhibiting a significant increase in lactate production over ALS and controls. Our results suggest that MS skin fibroblasts have an underlying stress phenotype, which may be disease specific. Interrogating MS skin fibroblasts may provide patient specific molecular insights and aid in prognosis, diagnosis, and therapeutic testing enhancing individualized medicine.

Abbreviations

2DG: 2-deoxyglucose; ACTB: actin beta; AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; ATF4: activating transcription factor 4; ATP: adenosine triphosphate; BIP: heat shock protein family A member 5: HSPA5/BIP; CHOP: DNA damage inducible transcript 3; CIS: clinically isolated syndrome; CNS: central nervous system; Ctrl: control; DMEM: Dulbecco’s modified eagle medium; DMFN: N-dimethylformamide; ECAR: extracellular acidification rate; EM: electron microscopy; ER: endoplasmic reticulum; FBS: fetal bovine serum; FCCP: carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone; GRP94: heat shock protein 90 beta family member 1: HSP90B1/GRP94; H2O2: hydrogen peroxide; HD: Huntington’s disease; iPSC: induced pluripotent stem cell; L-Gln: L-glutamine; MEM: Minimum essential medium; MS: multiple sclerosis; MSUD: maple syrup urine disease; MTT: 3-(4:5-dimethylthiazol-2-yl)-2:5-diphenyltetrazolium bromide; NEAA: nonessential amino acids; OCR: oxygen consumption rate; P16: cyclin dependent kinase inhibitor 2A: CDKN2A/P16; P21: cyclin dependent kinase inhibitor 1A: CDKN1A/P21; P53: tumor protein P53; PBS: phosphate-buffered saline; PD: Parkinson’s disease; PenStrep: penicillin-streptomycin; ROS: reactive oxygen species; RRMS: relapsing-remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis; TBP: TATA box protein; UPR: unfolded protein response; UV: ultraviolet radiation.