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Researchers identify mechanism of upper motor neuron degeneration in Amyotrophic Lateral Sclerosis.

For the first time, scientists have revealed a mechanism underlying the cellular degeneration of upper motor neurons, a small group of neurons in the brain recently shown to play a major role in ALS pathology.  ALS, or amyotrophic lateral sclerosis, is a fatal neuromuscular disorder marked by the degeneration of motor neurons, which causes muscle weakness and impaired speaking, swallowing and breathing that leads to paralysis and death. Defects in upper motor neurons, which send messages from the brain to the spinal cord to activate voluntary movement, may be a starting point for the disease.

In a new study Northwestern Medicine scientists begin to explain why upper motor neurons are vulnerable to degeneration. They developed a new mouse model for studying these cells, and found that increased stress in the endoplasmic reticulum (ER) is one culprit of upper motor neuron death.  The opensource study is published in Cerebral Cortex.

The team state that now the importance of upper motor neurons is appreciated, the medical community can develop therapies that improve their survival.  This study gives a target to go after, bringing the medical community one step closer to building effective treatment strategies.  The new model features mice without UCHL1 protein function, mutations in UCHL1 gene have previously been implicated in motor defects in human patients. Using in vitro and in vivo methods, the scientists discovered that loss of UCHL1 protein function affects protein regulation pathways, ER stress and upper motor neuron survival.

The team state that in this model, the timing and extent of upper motor neuron degeneration is unprecedented.  All the other neurons in the brain remain healthy, which means that this model will be very useful for studying the health of the upper motor neurons.

Upper motor neurons make up only about 150,000 of the 2 billion cells in the brain.  In mathematical terms, they’re insignificant, but their function is so important. They act as the spokesperson of the brain by collecting, integrating, translating and transmitting brain’s message to the spinal cord targets, and by doing so they initiate and modulate voluntary movement.

The lab has spearheaded research establishing that upper motor neurons are essential to ALS pathology. Previously, scientists thought that spinal motor neurons were more important in ALS pathology, that upper motor neuron death was a mere secondary effect. In 2012, the group showed that an early event in ALS is spine loss in the apical dendrites of upper motor neurons, where they make connections with other neurons in the brain. In 2013, the lab generated the first reporter line for upper motor neurons, to help scientists visualize them with a green fluorescent protein.

The team predict that now there is a model and reporter line, researchers have the tools to develop therapies directed at the upper motor neurons.  Survival requirements of these neurons cannot be ignored in ALS and in other diseases in which voluntary movement is impaired.

The team summise that the findings of the study could have applications to other neurodegenerative diseases that may share ER stress as an underlying cause.  Parkinson’s, Alzheimer’s and ALS are different branches of the same tree.  Subpopulations of patients may be developing these diseases due to the same dysfunctional cellular pathways. Finding a therapy for the pathway could help all of these patients.

Source:  Northwestern University Feinberg School of Medicine

 

Progressive CSMN degeneration in the UCHL1−/− mice.  (C and D) Representative images of matching coronal sections of WT (C) and UCHL1−/− mice (D) motor cortex, analyzed at P40, P65, P80, and P100, show progressive CSMN degeneration in UCHL1−/− mice. Boxed areas are enlarged below and to the right. Corticospinal Motor Neurons Are Susceptible to Increased ER Stress and Display Profound Degeneration in the Absence of UCHL1 Function.  Özdinler et al 2015.
Progressive CSMN degeneration in the UCHL1−/− mice. (C and D) Representative images of matching coronal sections of WT (C) and UCHL1−/− mice (D) motor cortex, analyzed at P40, P65, P80, and P100, show progressive CSMN degeneration in UCHL1−/− mice. Boxed areas are enlarged below and to the right. Corticospinal Motor Neurons Are Susceptible to Increased ER Stress and Display Profound Degeneration in the Absence of UCHL1 Function. Özdinler et al 2015.

 

 

 

 

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