Identifying novel pathogenic mechanisms for neurodegeneration.

By, Karen Ring and Brandon Tavshanjian.

Comparing a healthy brain to a brain with advanced Alzheimer's disease (AD) reveals severe degeneration in the AD brain.

Comparing a healthy brain to a brain with advanced Alzheimer’s disease (AD) reveals severe degeneration in the AD brain.

As humans age, fundamental processes that keep our cells and organ systems functioning properly begin to break down. In the aging brain, loss of function of or death of specific populations of brain cells can lead to neurodegenerative diseases such as Alzheimer’s disease, Huntington’s disease, and age-related memory impairment. Scientists are working hard to identify mechanisms that cause dysfunction/degeneration and disease in the brain using different models including invertebrates (ie. worms and flies) and vertebrates (ie. mice and rats) systems. Below are two recently published studies highlighting novel mechanisms of dysfunction that can cause neurodegeneration in humans.

Dysfunctional astrocytes cause age-related memory impairment in flies.

Age-related memory impairment (AMI) is thought to occur due to the build up of oxidative stress in cells. Cells are fueled by mitochondria, which generate energy through cellular respiration and regulate cellular metabolism. Cellular metabolism inevitably produces reactive oxygen species (ROS) that can build up in cells over time and cause damage. Oxidative stress has been linked to AMI in some models of aging. However, the relationship between oxidative damage and AMI has been controversial (see Hirano et al. who found that ROS are not involved in the onset of AMI in fruit flies).

Drosophila fruit flies are commonly used to model neurodegeneration.

Drosophila fruit flies are commonly used to model neurodegeneration.

In a recently published study by Yamazaki et al., the authors determined that AMI can be caused by the dysfunction of glial cells (astrocytes) in the brain by a mechanism that is independent of oxidative damage. Using a Drosophila fruit fly model of AMI, the authors determined that decreasing the amount of a specific protein (protein kinase A or PKA) in flies reduced the activity of an enzyme called pyruvate carboxylase (PC). PKA is expressed in neurons and regulates expression of PC, which is mainly expressed in astrocytes. The authors found that elevating levels of PC in flies decreased the neuromodulator chemical D-serine. D-serine is important for neuronal NMDA receptor activity, which is involved in learning and memory. Interestingly, the authors found that elevated PC expression in astrocytes was not caused by oxidative stress. Thus, the authors discovered a novel mechanism for AMI that is caused by the dysregulation of astrocyte neuromodulation.

Huntingtin regulates amino acid signaling to mTOR in Huntington’s Disease

A vexing question in Huntington’s Disease (HD) research has been to identify the normal, physiological function of the disease-causative huntingtin protein. Unlike many other inherited genetic diseases where it’s clear what important process the mutation is interfering with and thus which cellular or physiological process needs to be repaired, researchers still cannot agree on the actual dysfunction caused by the HD mutation.

Some new insight comes from the MacDonald and Subramaniam research groups, who’ve identified that both the native huntingtin protein and the protein carrying the disease mutation alter the ability of extracellular nutrients (the amino acid methionine) to activate a key protein that regulates energy expenditure in cells, mTOR. This process normally allows cells to alter their protein synthesis in response to extracellular nutrients; however, the authors found that both mutant huntingtin and wild type huntingtin increase the responsiveness of cells to nutrients, meaning that huntingtin might alter normal processes that control cell growth in the brain. This effect was particularly striking when cells expressed a fragment of the huntingtin protein thought to accumulate in the brain in late stages of the disease.

To show that this process played a role in the actual physiology of HD, the authors observed neurons in mice bearing the mutant huntingtin fragment, and showed that the same dysfunctional signaling was present. Furthermore, mice that expressed the fragment *and* had a mutation preventing normal regulation of mTOR activity developed much worse disease phenotypes, suggesting that the mTOR and huntingtin are connected during the development of HD.

This paper is the first example connecting the HD mutation to the function of mTOR, although other work has shown the ability of the huntingtin protein to disrupt other nutrient/growth factor signaling pathways. It will be interesting to see whether other researchers report similar results connecting huntingtin to the control of nutritional/growth factor signaling pathways in the brain.