The Brain Under Siege: To a Cure by Howard L. Weiner

Author:Howard L. Weiner [Weiner, Howard L.]
Language: eng
Format: epub
Tags: science, Life Sciences, Neuroscience, Medical, Neurology, Health & Fitness, diseases, Alzheimer's & Dementia
ISBN: 9781953295880
Google: uf0xEAAAQBAJ
Publisher: BenBella Books
Published: 2021-10-26T23:20:08.237964+00:00

IN SEARCH OF ADDITIONAL CULPRITS

Although most ALS patients do not have the abnormal SOD mutation that Bob Brown discovered, the mouse model of ALS with the SOD mutation has become a mainstay for investigating the disease. Additional mouse models have been generated using the other genes that have been identified. After these mouse models were created and clearly mimicked damage to the motor neuron that occurs in ALS, a major surprise in our study of ALS occurred with the discovery that it isn’t just an abnormality of the motor neuron that drives the disease: other cells are involved. Pioneering studies by Don Cleveland at the University of California San Diego and others showed that cells which are not motor neuron cells are important for driving the disease. This discovery opened up potential new avenues of therapy.

In a groundbreaking study published in 2006, Cleveland took the SOD mouse and, through sophisticated genetic manipulation, was able to create a mouse in which the abnormal SOD gene was present in the motor neurons but not in the microglial cells surrounding motor neurons. It was presumed that the toxic effects of SOD were due to the presence of abnormal SOD in the motor neurons, so removing the SOD from the microglial cells should have no effect on the disease. It was a little bit like asking, What’s important for vision, your eyes or your mouth? Cover up your eyes and you can’t see; cover up your mouth and you can still see. In the study, they were investigating if taking away the mutant SOD from the microglial cells would affect the motor neuron and disease progression.

The surprising answer was yes. Cleveland found that although decreasing SOD in the motor neurons delayed the onset of the disease, removing the SOD from the microglia also had an effect. Decreasing SOD in microglia did not affect disease onset but dramatically slowed disease progression. Thus, the abnormal SOD was doing something that impinged on the function of the microglia. In other words, dysfunction of other cells next to the motor neuron enhanced motor neuron damage, and microglial cells become activated at or before disease onset in the SOD mouse. This is an important discovery, because these experiments raised the possibility that targeting the microglial cell might help patients with ALS. Although the onset of ALS resulted from damage to motor neurons, Cleveland’s findings showed therapy could be successful by targeting a cell that was not a motor neuron. A Mr. Hyde–type microglial cell was a coconspirator and was contributing to the progression of ALS.

Further proof of Cleveland’s finding came from Stanley Appel’s laboratory at the Houston Methodist Hospital. Appel found that when normal microglia were transplanted into an ALS mouse, the normal microglia slowed motor neuron loss and animals lived longer. Understanding the important role of microglia in maintaining the health of the motor neuron also came from studies in our laboratory in which we removed microglia from the nervous system of normal mice and found that the animals developed an ALS-like disease without having an abnormality in the SOD gene.

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