UCLA researchers have proposed that molecular mechanisms behind each disability may differ, and that neuroprotective treatments tailored for each disability may be more effective than nonspecific treatments aiming to reduce a composite of different disabilities.

The research team focused on astrocytes, a type of brain cell that becomes activated in multiple sclerosis and plays several important roles in disease, examining gene expression in astrocytes in different regions.

Multiple sclerosis (MS) is an autoimmune, neurodegenerative disease, characterized by distinct disabilities affecting walking, vision, and cognition, to name a few. MS patients differ markedly from each other regarding which disability affects them the most.

Inflammation strips the myelin coating from nerve cell extensions, called axons, and connections at the ends of nerves, called synapses, are lost, together disrupting signaling and eventually causing permanent disability depending on where this occurs.

For multiple sclerosis, increasing cholesterol synthesis gene expression in astrocytes of the spinal cord can be a pathway to repair nerves that affect walking. This type of gene expression in specific cells and in specific regions can provide a more precise, neuroprotective approach than traditional treatments for neurological diseases.

The Disability-specific Discovery Approach

Working with a mouse model of MS, the research team assessed astrocytes in various regions of the brain and spinal cord known to be involved in walking, vision or cognition. They compared gene expression changes between regions that correspond to different disabilities.

In the spinal cord, an area that’s critical for walking, they found a decrease in the expression of cholesterol synthesis genes. Cholesterol does not leave the blood and enter the brain, instead it is made in astrocytes and plays a role in making myelin, the nerve coating, and synapses, the nerve connections.

[caption id=“attachment_93965” align=“aligncenter” width=“680”]cholesterol synthesis astrocytes Hypothetical effect of reduced cholesterol synthesis in astrocytes during EAE.
(A) Peripheral cholesterols cannot enter into the CNS due to the blood–brain barrier; thus, cholesterols in the CNS are synthesized de novo.
(B) In EAE, there is synaptic loss, axonal damage, and demyelination .
Credit: Noriko Itoh el al. CC-BY[/caption]

They hypothesized that while inflammation causes loss of myelin and synapses, it is the decrease in cholesterol synthesis gene expression in astrocytes that explains why lesions do not repair in multiple sclerosis. They treated MS mice with a drug that increased expression in cholesterol synthesis genes - and this resulted in improved walking ability.

This disability-specific discovery approach represents a strategy for finding neuroprotective treatments for neurodegenerative diseases that are tailored to repair damage for each disability, one at a time, in contrast to a “one size fits all” treatment approach.

The research was supported by Conrad N. Hilton Foundation Grants, a NIH Grant, California Community Foundation Grant, and funding from the Tom Sherak MS Hope Foundation, the Rhoda Goetz Foundation for Multiple Sclerosis, and other partners of the University of California, Los Angeles MS Program.

Noriko Itoh, Yuichiro Itoh, Alessia Tassoni, Emily Ren, Max Kaito, Ai Ohno, Yan Ao, Vista Farkhondeh, Hadley Johnsonbaugh, Josh Burda, Michael V. Sofroniew, and Rhonda R. Voskuhl Cell-specific and region-specific transcriptomics in the multiple sclerosis model: Focus on astrocytes PNAS 2017 ; published ahead of print December 26, 2017, doi:10.1073/pnas.1716032115

Image: Dr David Furness, Wellcome Images

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