Multiple Sclerosis Attacks Brain’s ‘Projection Neurons’

Discovery Could Inform Future MS Immunotherapies

By Nicholas Weiler

Brain damage associated with multiple sclerosis (MS) specifically targets a common class of brain cells called projection neurons, according to a new international study by scientists at UC San Francisco, Cambridge University, and the University of Heidelberg.

MS is a progressive neurodegenerative disease of the brain and spinal cord that affects over 2 million people worldwide with impairments in vision, movement, and cognitive abilities, among other symptoms. Many of MS’s symptoms are caused when the immune system gradually attacks the protective insulation that ensheathes nerve fibers, causing a breakdown of communication in the nervous system. 

MS is also known to kill off brain cells directly – particularly in the wrinkly neocortex on the brain’s surface, which is the seat of our higher cognitive abilities – but so far it hasn’t been clear whether all kinds of cells suffer equally or whether there is a certain class of neuron that is particularly affected, which could lead to new clues for MS treatment.

In the new study, published July 17, 2019, in Nature, the researchers studied areas of cortical damage in MS patient brain tissue, using single-cell genetics techniques developed at UCSF, to identify the specific cell types that bear the brunt of the damage. 

Arnold Kriegstein, MD, PhD, study’s co-corresponding author.

They found that the worst-affected cells are so-called projection neurons in the outermost layers of the cortex, which play a role in linking together far-flung cortical regions into a networked whole. The research also suggested that these cells die of chronic cellular stress and may trigger a particular form of inflammation in the brain that could be targeted by immune therapies to minimize brain damage in MS patients, though these findings will require further study.

“These new techniques have wide applicability in the understanding of human neurodevelopmental and neurological disorders and are providing new insight into not only MS, but also autism spectrum disorder, which we studied recently using a very similar approach,” said Arnold Kriegstein, MD, PhD, the study’s co-corresponding author, who is professor of neurology and director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.

The research was overseen by David Rowitch, MD, PhD, professor and head of the Department of Paediatrics at the University of Cambridge and an adjunct professor of pediatrics and neurological surgery at UCSF. Kriegstein and UCSF postdoctoral scholar Dmitry Velmeshev, PhD, developed the techniques used to analyse the genetic code within individual brain cells. Valmeshev, formerly in Kriegstein’s lab and Lucas Schirmer, MD, formerly in Rowitch’s lab and now a faculty member at the University of Heidelberg were the study’s co-first authors.

See Cambridge University’s press release for more details on the study.