Cell: A Promising Trend That Avoids Foreign Rejection and Replaces Damaged Neurons on self
This is a confocal micrograph of a primary human fibroblast cell grown in culture stained blue for actin, a highly abundant protein that makes up the cytoskeleton of cells. Mitochondria are shown in green.
According to some statistics, it is estimated that 25% Americans will suffer from a neurodegenerative disease in whole life, from Alzheimer's and Parkinson's to multiple sclerosis and amyotrophic lateral sclerosis (or Lou Gehrig's disease). Now these diseases can be controlled but not cured. And the treatment focus is to preserve neurons or slow the rate of degeneration.
People suppose to replace lost neurons using embryonic stem cells, but there are still a lot of challenges, for example, the usage of foreign DNA and the low efficacy and complexity.
Recently a new study identified that the repression of a single protein in ordinary fibroblasts is sufficient to directly convert the cells -- abundantly found in connective tissues -- into functional neurons. The findings, was published on Cell, which could have far-reaching implications for the development of new treatments for neurodegenerative diseases like Huntington's
For years, scientists have significantly improved the ability to induce pluripotent stem cells to become almost any type of cell, especially for the step in many diverse therapeutic efforts. The new study focuses upon the surprising and singular role of PTB, an RNA-binding protein long known for its role in the regulation of alternative RNA splicing.
Thus scientists were working on ways to manipulate PTB as it appears to be a kind of master regulator, which might eventually avoid some of these problems by creating new neurons in patients using their own cells adjacent deteriorating neurons.
In in vitro experiments, scientists described the protein's notable regulatory role in a feedback loop that also involves microRNA that modulates the expression of up to 60 percent of genes in humans. Approximately 800 miRNAs have been identified and characterized to various degrees.
One of these miRNAs, known as miR-124, specifically modulates levels of PTB during brain development. The researchers found that when diverse cell types were depleted of PTB, they became neuronal-like cells or even functional neurons -- an unexpected effect. The protein, they determined, functions in a complicated loop that involves a group of transcription factors dubbed REST that silences the expression of neuronal genes in non-neuronal cells. REST is expressed in cells everywhere except in neurons. PTB is itself a target of miR-124, but also acts as a break for this microRNA to attack other cellular targets that include REST, which is responsible for repressing miR-124.
According to researchers, it's not known which neuronal signal or signals turn on the loop, which in principle can happen at any point in the circle. But the ability to artificially manipulate PTB levels in cells, inducing them to become neurons, offers tantalizing possibilities for scientists seeking new treatments for an array of neurodegenerative diseases.
In non-neuronal cells, REST keeps miR-124 down and PTB enforces this negative feedback loop, but during neural induction, miR-124 is induced, which diminishes PTB, and without PTB as a break, REST is dismantled, and without REST, additional miR-124 is produced. This loop therefore becomes a positive feed forward, which turns non-neuronal cells into neurons.
This research was partially funded by NIH.
Tags: Fibroblast Cell, iPS, Stem Cells, Neurodegenerative Diseases, REST, PTB, microRNA