Glue-ing the brain

Previously unexplored parts of the brain could hold the cure for ALS, MS or memory-related disorders

WrittenBy:Science Desk
Date:
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By Navneet A Vasistha

In 1898, William Ford Robertson, a Scottish pathologist working in the Royal Edinburgh Asylums published his work on an undescribed group of brain cells.

A young 32-year-old man, he had been staining brain slices with platinum, palladium and silver in a method like that of Camillo Golgi. When platinous oxide (PtO2) finally brought him success, he wrote:

“…I have found throughout the cortex and in the white matter, numerous small branching cells of a very characteristic aspect… in these peculiar and unbranched cells we have a special tissue-element belonging to the nervous system which has not hitherto been distinguished as such.” – A Textbook of Pathology in Relation to Mental Diseases (1900); W. Ford Robertson

For reasons unknown, he went on to call them ‘mesoglia’, referring to a kind of immune cell found in the brain. By early 1900s, Robertson had shifted to studying the role of bacterial infections in mental illness and then to penning a book titled Walks from Wooler. He soon passed away in 1923, and though he published his results based on the use of platinum, those using silver never made it into print.

In 1921, Pío del Río-Hortega; a Spanish neuroscientist identified a cell type in the brain he called ‘oligodendroglia’ (glia with few branches). Using a solution of silver carbonate, over the next decade, he went on to describe this cell in greater detail and spurred other researchers to work on it. When in 1932 his colleague, the Canadian-American Wilder Penfield, compared slides of both Robertson and del Rio-Hortega’s preparations, he remarked:

“After examining an original preparation of Robertson and comparing it with sections stained by Rio-Hortega’s method, I am convinced that the mesoglia of Robertson and the oligodendroglia of Rio-Hortega are the same, as pointed out by the latter author. Preparations by both methods show cells which appear in rows in the white matter, are very numerous and provided with expansions similar in form and arrangement. Likewise, the description and drawings provided by Robertson… correspond with the oligodendroglia of del Rio-Hortega” – Oligodendroglia and it’s Relation to Classical Neuroglia (1932): Wilder Penfield

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Figure: Robertson’s drawings from his textbook showing oligodendrocytes stained with his mixture of Platinous oxide.

Despite such early enthusiasm, glia were not studied for the next 50 years. The exact reason why this was so, is hard to pinpoint; it is likely due to a support for neurons being the major cell type of the brain that was responsible for all behaviour, cognition and movement. As glia were described to produce a meshwork around neurons, they were thought to play a supportive role and hence called named after the Greek word for glue.

Today, the term ‘glia’ refers to astrocytes (star-shaped cells), microglia (small glia; cells with immune functions) and of course oligodendrocytes. Why are oligodendrocytes specifically interesting then? Well, for starters, they are the only cells in the central nervous system (CNS) to wrap around the long tube-like axons that carry information from the nerve cell body. These wraps are called ‘myelin’ and are composed of 80 per cent fatty acids and the rest proteins. By wrapping around axons, not only do they provide a physical support to the nerves preventing damage but also increase in the speed of nerve impulse conduction by 10 times. This is important especially in long-range connections such as those of motor neurons that traverse almost a meter between our brains and spinal cords.

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Figure: Transmission Electron Micrograph of oligodendrocyte myelin (dark stained, outer) ensheathing neuronal axons (pale stained, inner) from a mouse brain. Scale bar on left bottom corner shows 100 nanometers.

Recent studies have shown that oligodendrocytes also provide metabolic support to axons by shuttling nutrients 3,4. This allows the energy guzzling axons to continue operating even when the nerve cell is itself running low on fuel. In fact, the absence of this shuttling can be detrimental to nerve cells and has been noticed in some forms of Motor Neuron Disease (also called Amyotrophic Lateral Sclerosis; ALS).

However, the single example that highlights the importance of oligodendrocytes is gauged from the study of disorders such as Multiple Sclerosis (MS), Leukodystrophy and Vanishing White Matter Disease (VWM). In such disorders, there is a loss of the wrapping around axons leading to tremors, cognitive changes, loss of voluntary control of body functions and paralysis. In order to find cures for such disorders, scientists have taken to making oligodendrocytes using stem cells from patients with such disorders. Along with new developments in microscopy and computer aided analysis, scientists are screening thousands of drug compounds to identify those that could slow, stop or even reverse the effects of these disorders 5,6

Remarkably, scientists have also shown that it is possible to populate the brain of a mouse with transplanted oligodendrocytes derived from human stem cells 7. These mice survive longer and also perform much better on motor and cognition tasks compared to those that don’t receive these grafts. While further research is required to assess long-term safety of such interventions, these studies provide a compelling argument for the possibility of treating debilitating disorders such as MS by transplanting new oligodendrocytes into patients.

Robertson and del Rio-Hortega might have never thought their research would have such profound implications for human health but in essence, scientific progress takes places through such unconnected works coming together. Cells that were once believed to merely ‘glue’ the brain together are now thought to play important roles in memory, cognition and movement.

REFERENCES

  1. Robertson W.F A Textbook of Pathology in Relation to Mental Diseases (1900).
  2. Penfield W Oligodendroglia and it’s Relation to Classical Neuroglia (1932).
  3. Lee, Y. et al. Nature 487, 443–448 (2012).
  4. Fünfschilling, U. et al. Nature 485, 517–521 (2012).
  5. Najm, F.J. et al. Nature 522, 216–220 (2015).
  6. Deshmukh, V.A. et al. Nature 502, 327–332 (2013).
  7. Windrem M et al. Cell Stem Cell 2(6), 553-565 (2008)
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