New understanding of degeneration of brain cells in patients with Alzheimer's, Huntington's, and Parkinson's diseases

A ground-breaking new research approach to understanding the cellular processes of Alzheimer's and other degenerative diseases has revealed a promising pathway to the development of new types of drugs for these diseases.

The discovery, made in the laboratory of Ratnesh Lal, research scientist in the Neuroscience Research Institute (NRI) at the University of California, Santa Barbara, is published in this week's online issue of the Proceedings of the National Academy of Sciences (PNAS).

The research describes a new way of understanding the degeneration of brain cells in patients with Alzheimer's, Huntington's, and Parkinson's diseases, as well as other degenerative diseases. Misfolded proteins in the cell membrane, and subsequent changes in the electrical properties of cells, provide the explanation for the cell degeneration. Specific three-dimensional structures of misfolded proteins are embedded in the cell membrane.

"It has long been thought that amyloid plaque, which has been studied for 30 years, was the cause of Alzheimer's disease," said Lal. "Plaque isn't the cause." He explained that the fibers of plaque are too large to directly affect small cells.

The answers may come from small globs of misshapen, misfolded proteins that make well-defined holes in cell membranes and disrupt their electrical activity, according to the study.

Amyloid protein is a sticky, globular substance created when normal cellular proteins become twisted and contorted into abnormal shapes. While amyloid formation has been associated with diseases like Alzheimer's, Parkinson's, and Huntington's, scientists have puzzled over whether and how it actually kills cells and causes disease. To gain insight into this mysterious process, Lal and his research team examined the three-dimensional structure of several different proteins associated with these diseases. The researchers observed that all of the proteins folded into structures resembling ion channels, or pores within cell membranes. These pores control the electrical properties of the cell by regulating the flow of charged particles (ions) such as calcium.

When embedded into artificial membranes, the misfolded proteins were able to produce electrical currents, confirming their similarity to ion channels. Since abnormal ion balance is known to disrupt cell function and cause degeneration, these results provide proof of a possible mechanism by which amyloid formation may lead to the cellular destruction seen in these neurodegenerative diseases.

"These ion channels could serve as a model system for designing preventive and therapeutic drugs," said Lal. "You don't need large aggregates of these amyloid proteins, the plaque, to have this disruption. Rather, small aggregates, when in contact with membrane, form ion channels and allow passage of ion current. By controlling activity and designing specific drugs to regulate these channels, we might be able to prevent and/or treat various diseases related to the amyloids."

These findings provide a major piece of the puzzle about the underlying protein misfolding associated with these degenerative diseases. Besides the diseases already mentioned, other degenerative diseases that also result from misfolded proteins include cystic fibrosis, type II diabetes, cerebrovascular dementia, arthritis, tuberculosis, as well as British and Danish famial dementias.

The researchers used atomic force microscopy (AFM) to view the ion channels. By using the AFM they were able to view these "bio-nano" molecules. The AFM allows for a look at these very small channels, which would be very difficult if not impossible to see in their native, cell-like environment with electron microscopy.

In addition to Lal, the authors of this path-breaking paper are: Arjan Quist and Ivo Doudevski of the NRI at UCSB; Han Lin of the University of Pittsburgh; Rushana Azimova and Bruce Kagan of the University of California, Los Angeles; and Douglas Ng, Blas Frangione, and Jorge Ghiso of New York University.

Comments

  1. Wendy Wendy United States says:

    This is a post for my friend:

    My daughter is 19 years old, 13 years ago when she was 6 years old, we began to find her has difficulty in muscle movement.
    Her back vertebra has winded, and she couldn’t sit straight. A major surgery has been done on her back vertebra (to put into straight steel to replace the vertebra).
    Over the last several years, her condition got worse. Now she can only sit, can not walk along. Her muscle’s movement strength is deteriorating.  Doctor determined the disease to be “brain cell degeneration”.

    We are trying to find the root cause of her symptom. Can you help? She is located in Shanghai, China

  2. Yinka Yinka Canada says:

    I want to study the degeneration of brain cells, so I just have a few questions.

    1. Do your new findings of brain cell degeneration, explain what happens in patients with the diseases mentioned, or just in everyday general life?

    2. Does the concept about degeneration caused by spurred activity in the Rho protein go along the same lines as your concept being presented, or does it go against it, or have nothing to do with it?

    Thank you for your time and contribution to the medical field

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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