Abstract
Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are found in lesions of multiple sclerosis (MS) and of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and may contribute to the neuronal loss that underlies permanent impairment. These pathological changes are due to the neuroinflammation that characterizes MS and the strong interplay between the ER and mitochondria. We investigated whether immunomodulatory drug glatiramer acetate (GA) can reduce these changes in the spinal cords of chronic EAE mice by using routine histology, immunostaining, and electron microscopy. EAE spinal cord tissue exhibited increased infiltration/inflammation (upregulation of proinflammatory cytokines), demyelination, mitochondrial dysfunction (increased fission, decreased fusion, and increased biogenesis), ER stress, downregulation of NAD+ dependent pathways, and increased neuronal death. GA reversed these pathological changes, suggesting that immunomodulating therapy can attenuate ER stress, mitochondrial dysfunction, apoptotic cell death, and demyelination in the CNS and increase NAD+ utilizing activities by suppressing neuroinflammation.
Competing Interest Statement
Partial funding for the study was provided by an investigator-initiated grant to Dr. Makar from Teva Neuroscience, Inc. which markets glatiramer acetate as a treatment for multiple sclerosis. Guda, Ray, Andhavarapu, Nimmagadda, Gerzanich, Simard, and Bever declare no competing interests.
Abbreviations
- MS
- multiple sclerosis
- CNS
- central nervous system
- EAE
- experimental autoimmune encephalomyelitis
- UPR
- unfolded protein response
- MRI
- magnetic resonance imaging
- ROS
- reactive oxygen species
- ER
- endoplasmic reticulum
- MAM
- mitochondria associated membrane
- NAD
- nicotinamide dinucleotide
- GA
- glatiramer acetate
- BBB
- blood brain barrier
- Ca2+
- calcium ions
- MOG
- myelin oligodendrocyte glycoprotein
- CFA
- complete Freund’s adjuvant
- PBS
- phosphate-buffered saline
- IL-17
- interleukin 17
- MBP
- myelin basic protein
- MFN-2
- mitofusin-2
- Fis-1
- fission-1
- DNM1-L
- dynamin-like protein
- PGC1-a
- Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
- FOXO-1
- Forkhead box protein 1
- TFAM
- mitochondrial transcription factor A
- SIRT
- sirtuin
- NAMPT
- Nicotinamide phosphoribosyltransferase
- BAX
- Bcl-2-associated X protein
- CHOP
- CCAAT-enhancer-binding protein homologous protein
- PERK
- protein kinase RNA-like endoplasmic reticulum
- PINK1
- PTEN-induced kinase 1
- VDAC-1
- Voltage-dependent anion channel 1
- PACS2
- Phosphofurin Acidic Cluster Sorting Protein 2
- eIF2α
- eukaryotic translation initiation factor 2 subunit alpha