Featured Research

from universities, journals, and other organizations

Teasing Out The Early Steps Of Neurodegeneration

Date:
January 26, 2000
Source:
Howard Hughes Medical Institute
Summary:
Researchers studying mice that develop a neurodegenerative disorder similar to spinocerebellar ataxia type 1 (SCA1) have pinpointed abnormalities in gene expression that occur long before signs of the disease appear. The researchers believe that their discovery could lay the groundwork for tracing the cascade of malfunctions that ultimately leads to the degeneration of specific groups of neurons in patients with SCA1.

January 24, 2000 — Researchers studying mice that develop a neurodegenerative disorder similar to spinocerebellar ataxia type 1 (SCA1) have pinpointed abnormalities in gene expression that occur long before signs of the disease appear. The researchers believe that their discovery could lay the groundwork for tracing the cascade of malfunctions that ultimately leads to the degeneration of specific groups of neurons in patients with SCA1.

HHMI investigator Huda Zoghbi at the Baylor College of Medicine and colleagues reported their findings in the February 2000 issue of Nature Neuroscience.

In 1993, Zoghbi and her collaborator Harry Orr of the University of Minnesota found that SCA1 is caused by a "genetic stutter" of the three-nucleotide DNA sequence CAG. Genes that contain this stutter have an unusually high number of CAG repeats, which in turn causes them to produce proteins with an abnormally long glutamine tract. A normal SCA1 gene has about 30 CAG repeats, which are interrupted by another triplet repeat sequence. People who have SCA1, however, carry a gene with 40 to a hundred uninterrupted CAG repeats.

SCA1 is one of eight neurodegenerative diseases—the most well known of which is Huntington's disease—that is caused by this type of mutation. Somehow, the "polyglutamine" proteins cause severe degeneration in specific groups of neurons, which vary from one disease to the next. Patients with SCA1 suffer the worst damage in their cerebellar Purkinje cells, and consequently lose their balance and motor coordination. Loss of muscle control worsens steadily until patients are no longer able to eat or to breathe.

In 1998, Zoghbi and her colleagues showed that the abnormal SCA1 protein, ataxin-1, accumulates in the cell nucleus where it presumably impairs normal functions.

"After those studies, we were left with two major questions," said Zoghbi. "We wanted to understand how the accumulation of ataxin-1 affected the normal function of the cell's nucleus. And, we wanted to understand why Purkinje cells were most severely affected, even though ataxin-1 is present in all brain cells."

To answer these questions, the researchers used a mouse model of SCA1 that mimicked the human disease. Like humans with SCA1, the mice were born with a SCA1 gene containing an excessive number of glutamine repeats and suffered Purkinje cell degeneration.

Using a technique known as "PCR-based cDNA subtraction," which allowed them to compare gene expression in normal and SCA1 mice, Zoghbi and colleagues were able to pinpoint other genes whose expression pattern was altered by the abnormal SCA1 gene. "We found six neuronal genes, all highly abundant in Purkinje cells, that were downregulated at a surprisingly early stage in the disease," said Zoghbi. "In fact, the earliest gene, called PCCMT, was downregulated only one day after the SCA1 gene turns on. Others were downregulated a few days or weeks afterward."

Also surprising, said Zoghbi, was that several of the downregulated genes produced proteins that helped regulate calcium levels in neurons. "This finding suggests that calcium physiology and homeostasis is altered in the affected Purkinje cells," said Zoghbi. Calcium is crucial to a neuron's ability to send and receive electrochemical signals.

The researchers found that a mouse homolog of the human gene called aACT-1, which is perturbed in patients with Alzheimer's and Huntington's diseases, was also upregulated in their transgenic mice. According to Zoghbi, the discovery that this gene is affected suggests a possible commonality among the diseases in the reactions of brain cells to earlier malfunctions.

In comparing the gene expression profiles from their mouse model to gene expression in human tissue from SCA1 patients, Zoghbi and her colleagues found similarities in the patterns of expression of the affected genes.

"In humans, these neurodegenerative diseases do not show up until later in life, so the changes in cells must be very subtle," said Zoghbi. "Thus, our identification of a number of genes that seem important in these early stages could offer an important foundation for understanding the earliest molecular events that eventually cause the cell to become dysfunctional and die."

Future experiments, said Zoghbi, will concentrate on understanding how the mutant ataxin-1 protein interacts with genes in the nucleus. In particular, said Zoghbi, she and her colleagues would like to understand the function of PCCMT, the first gene to be downregulated, since it might be a key to later malfunctions in the cell.

Zoghbi emphasizes that the scientists' basic discoveries will not likely lead to direct clinical applications.

"Nevertheless, if we could understand the early perturbations in calcium homeostasis in these Purkinje cells, and if these could be pharmacologically altered, these basic findings might ultimately aid treatment of this disease," she said.


Story Source:

The above story is based on materials provided by Howard Hughes Medical Institute. Note: Materials may be edited for content and length.


Cite This Page:

Howard Hughes Medical Institute. "Teasing Out The Early Steps Of Neurodegeneration." ScienceDaily. ScienceDaily, 26 January 2000. <www.sciencedaily.com/releases/2000/01/000126080111.htm>.
Howard Hughes Medical Institute. (2000, January 26). Teasing Out The Early Steps Of Neurodegeneration. ScienceDaily. Retrieved July 31, 2014 from www.sciencedaily.com/releases/2000/01/000126080111.htm
Howard Hughes Medical Institute. "Teasing Out The Early Steps Of Neurodegeneration." ScienceDaily. www.sciencedaily.com/releases/2000/01/000126080111.htm (accessed July 31, 2014).

Share This




More Health & Medicine News

Thursday, July 31, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Health Insurers' Profits Slide

Health Insurers' Profits Slide

Reuters - Business Video Online (July 30, 2014) Obamacare-related costs were said to be behind the profit plunge at Wellpoint and Humana, but Wellpoint sees the new exchanges boosting its earnings for the full year. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com
Concern Grows Over Worsening Ebola Crisis

Concern Grows Over Worsening Ebola Crisis

AFP (July 30, 2014) Pan-African airline ASKY has suspended all flights to and from the capitals of Liberia and Sierra Leone amid the worsening Ebola health crisis, which has so far caused 672 deaths in Guinea, Liberia and Sierra Leone. Duration: 00:43 Video provided by AFP
Powered by NewsLook.com
At Least 20 Chikungunya Cases in New Jersey

At Least 20 Chikungunya Cases in New Jersey

AP (July 30, 2014) At least 20 New Jersey residents have tested positive for chikungunya, a mosquito-borne virus that has spread through the Caribbean. (July 30) Video provided by AP
Powered by NewsLook.com
Xtreme Eating: Your Daily Caloric Intake All On One Plate

Xtreme Eating: Your Daily Caloric Intake All On One Plate

Newsy (July 30, 2014) The Center for Science in the Public Interest released its 2014 list of single meals with whopping calorie counts. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

    Environment News

    Technology News



      Save/Print:
      Share:

      Free Subscriptions


      Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

      Get Social & Mobile


      Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

      Have Feedback?


      Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
      Mobile: iPhone Android Web
      Follow: Facebook Twitter Google+
      Subscribe: RSS Feeds Email Newsletters
      Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins