Researchers from the University of Exeter (UK) and the University of Alberta (Canada) have discovered a cellular mechanism that could be a cause of multiple sclerosis (MS), and a potential future treatment target. The findings were recently published in the Journal of Neuroinflammation.
MS affects around 2.5 million people worldwide. Its cause has eluded researchers, resulting in a lack of treatments. The treatments that are available treat the symptoms of MS, which can include muscle spasms, mobility problems, pain, fatigue and problems with speech.
Endoplasmic reticulum (ER) stress is a hallmark of neurodegenerative diseases. However, it can manifest in a variety of ways, from impairment of the unfolded protein response to altered mitochondrial dynamics and apoptosis.
While these mechanisms are little understood, it is possible that the mitochondria-associated membrane (MAM), the contact between the ER and mitochondria, is involved. The current research saw the combination of clinical and laboratory experiments to clarify how mitochondria become defective in MS sufferers.
Studying human and mouse brain tissue, the group demonstrated that the protein Rab32 is abundant in the brains of those with MS and experimental autoimmune encephalomyelitis, but virtually absent from healthy brain cells. Rab32 is a known regulator of the MAM, mitochondrial dynamics and apoptosis.
They went on to demonstrate that, in the presence of Rab32, miscommunication between the endoplasmic reticulum and mitochondria results in toxicity. “High Rab32 expression shortens neurite length, alters mitochondria morphology and accelerates apoptosis/necroptosis of human primary neurons and cell lines,” noted the authors.
While the cause of Rab32 influx is yet to be elucidated, these findings highlight Rab32 as a potential treatment target. “Our exciting new findings have uncovered a new avenue for researchers to explore. It is a critical step, and in time, we hope it might lead to effective new treatments for MS,” commented Paul Eggleton, one of the study authors (University of Exeter).
The team hopes future research will be able to investigate whether inhibition of Rab32 in inflamed CNS could inhibit neurodegeneration.
Sources: Haile Y, Deng X, Ortiz-Sandoval C et al. Rab32 connects ER stress to mitochondrial defects in multiple sclerosis J. Neuroinflammation 14(1), 29 (2017); http://www.exeter.ac.uk/news/research/title_578807_en.html