Posts tagged neurodegenerative disorders

Changes in the ability to smell and taste can be caused by a simple cold or upper respiratory tract infection, but they may also be among the first signs of neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Now, new research from the Perelman School of Medicine at the University of Pennsylvania  has revealed an association between an impaired sense of smell and myasthenia gravis (MG), a chronic autoimmune neuromuscular disease characterized by fluctuating fatigue and muscle weakness. The findings are published in the latest edition of PLOS ONE.

Most humans experience five types of tastes: sweet, salty, sour, bitter, and savory.  The sense of taste is mediated by taste receptor cells which are bundled in our taste buds. “Sour” and “bitter” taste sensations alert the body to harmful foods that have spoiled or are toxic. But based on genetics, up to 25 percent of the population cannot detect certain bitter flavors (non-tasters), 25 percent can detect exceedingly small quantities (super-tasters), and the rest of us fall somewhere between these two extremes.

So what exactly does drinking a cup of bitter coffee have to do with chronic sinus infections, which account for approximately 18-22 million physician visits in the U.S. each year?  Recent investigations have shown that these taste receptors (T2Rs) are also found in both upper and lower human respiratory tissue, likely signaling a connection between activation of bitter tastes and the need to launch an immune response in these areas when they are exposed to potentially harmful bacteria and viruses.

“With this information in mind, we wanted to better understand the exact role that bitter taste receptors play in the upper airway, especially between these super and non-tasters,” says Noam Cohen, MD, PhD, assistant professor of Otorhinolaryngology: Head and Neck Surgery, staff physician at the Philadelphia VAMC, and senior author of the new study.

(Source: medicalxpress.com)

July 11, 2012

(Medical Xpress) — Johns Hopkins researchers say they have discovered that the central nervous system’s oligodendroglia cells, long believed to simply insulate nerves as they “fire” signals, are unexpectedly also vital to the survival of neurons. Damage to these insulators appears to contribute to brain injury in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease for the Yankee baseball great who died from the disease.

The discovery, described online in the journal Nature, suggests that a previously unknown — and unexpected — function of these cells is to supply nutrition to the principal brain cells, neurons. This new pathway may prove to be an important and novel therapeutic target for ALS, the researchers say, and potentially other diseases that attack the body’s nerve fibers, such as multiple sclerosis.

"More than 100 years after their discovery, we have now found a fundamentally new property in the way oligodendroglia work in the brain, laying the foundation for a new approach to try to treat debilitating neurodegenerative diseases,” says Jeffrey D. Rothstein, M.D., Ph.D., a professor of neurology and neuroscience at the Johns Hopkins University School of Medicine, and the study’s leader. “We’ve added a whole new category to what they do in the brain.”

The cells responsible for the transfer of information and electrical impulses around the body, neurons work by transferring electrical charges from neuron to neuron. Axons, the wire-like extensions of the neurons, help move the messages, in some cases over many feet, from cell to cell. Oligodendroglia insulate axons, like rubber coating around an electrical wire, to speed up the conduction of information. Axonal death is a hallmark of ALS and most other neurodegenerative disorders, Rothstein says.

Rothstein and his colleagues say the other principal brain cells, the astroglia, were believed to be primarily responsible for providing energy to neurons in the form of glucose, but their experiments show that oligodendroglia are surprisingly crucial in feeding neurons — in the form of less energy-rich lactate, without which neurons and their axons die. Lactate has long been seen as a minor player in this process, but the Johns Hopkins team says it appears to be far more important to nerve cell survival. Moreover, they found that the protein MCT1, the dominant transporter of lactate in the brain, is only found in oligodendroglia.

Rothstein says their discovery was rooted in experiments during which scientists, using mice, knocked out the gene that makes the MCT1 protein and saw axons begin to die, even though they were still getting plenty of glucose.

As part of these experiments, the researchers engineered mice whose cells would light up if they were expressing MCT1. The scientists then determined that only oligodendroglia cells lit up, showing that MCTI is located on this type of cell alone. They also knocked out the MCT1 in cell cultures and found that neurons would begin to die, but would recover when fed lactate, proving the importance of MCT1 in providing this nutritional compound. They conducted the same experiments in mice and got similar results.

Finally, the researchers turned their attention to ALS, a disease where they had recently uncovered abnormalities related to oligodendroglia. In ALS mice, they found that MCT1 was missing in brain cells well before the disease developed, and they found similar results in ALS patients. Rothstein says the findings suggest that oligodendroglia injury — specifically injury to the mechanism that produces MCT1 — may be an important event in the onset and progression of ALS.

Rothstein, who is director of the Johns Hopkins University School of Medicine’s Brain Science Institute, says he hopes further research can establish that the activation of MCT1 in people will protect axons in those with ALS and other degenerative diseases.

Provided by Johns Hopkins University School of Medicine

Source: medicalxpress.com

June 27th, 2012

Researchers from the Huck Institutes’ Center for Cellular Dynamics, led by Center director Melissa Rolls, have found that a neuroprotective pathway initiated in response to injured or stressed neural axons serves to stabilize and protect the nerve cell against further degeneration.

Neurons, or nerve cells, typically have a single axon that transmits signals to other neurons or to output cells such as muscle tissue, and as these axons extend for long distances within the cell, they are thus at risk for injury.

Furthermore, if an axon is damaged, its parent neuron can no longer function; and since many animals develop only one set of neurons, those neurons will mount major responses to axon injury.

“Neurons are quite remarkable cells,” says Dr. Rolls. “Most of them need to survive and function for your entire lifetime. Maybe then it shouldn’t be a surprise that they do not give up easily when damaged or stressed, but it is amazing to be able to watch them fight back and stabilize themselves.”

Neurons expressing a toxic form of spinocerebellar ataxia type 3 (SCA3) with protective pathway enabled (left) and blocked (right). Image adapted from Penn State press release image with credit to Melissa Rolls. Click for larger view and original image from Penn State.

Dissecting Drosophila

Dr. Rolls and her team set out to understand these cellular responses to axon injury by observing the effects of severing fruit fly axons with a laser.

What they found was that the neurons responded to the injury by increasing production of microtubules — cytoskeletal components responsible for maintaining cell structure and providing platforms for intracellular transport — in order to stabilize the neural dendrites, which are the branched structures responsible for transmitting signals to the nerve cell body.

In addition to acute injury response, the team also investigated neurons’ response to long-term axon stress — and found similar results.

Accumulation of misfolded proteins or protein aggregates — responsible for neurodegenerative diseases such as Huntington’s disease and spinocerebellar ataxia — induced the same type of cytoskeletal changes as acute axon injury.

Dr. Rolls elaborates: “The assays that we use are all in vivo, so we can literally watch what the neurons do in different scenarios, including cutting of their axon. Being able to observe the cellular responses gave us some ideas we would not have come up with otherwise. For example, it is not intuitive that expressing a protein that causes degeneration would trigger the cell to turn on a pathway that delays degeneration.”

The neuroprotective pathway

The video below shows the difference in microtubule dynamics between cells expressing a non-toxic form of the huntingtin protein (left) and cells expressing a disease-causing form (right).

[Video: Axon injury and stress trigger a microtubule-based neuroprotective pathway]
Credit: Melissa Rolls, Director, Center for Cellular Dynamics

Conclusions and implications

Based on their observations, the authors suggest that this pathway represents an endogenous neuroprotective response to axon stress — and could potentially be developed into a diagnostic tool for the detection of early stages of neurodegenerative disease, or even utilized in novel therapies for such illnesses.

“We don’t yet know if all types of neurodegenerative disease trigger this type of stabilization pathway; but if there are some diseases in which it is off, then it may be beneficial to try to turn it on to help the neurons resist degeneration,” says Dr. Rolls.

The results of the study have been published in Proceedings of the National Academy of Sciences.

Source: Neuroscience News