Gene linked to Lou Gehrig's disease may also cause common dementia

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Washington, Feb 21 : Researchers at Washington University chool of Medicine in St. Louis have found that a gene linked to nherited amyotrophic lateral sclerosis (ALS) or Lou Gehrig's isease, may also play a role in dementia.

The gene in question has been identified as TDP-43.

The study is led by Nigel Cairns, Ph.D., research associate rofessor of neurology and pathology and immunology.

"The potential link to sporadic ALS is particularly interesting. f we can confirm TDP-43's association with inherited ALS, utating this gene may give us a way to model sporadic ALS in aboratory animals for the first time. That could give us a otent tool for better understanding ALS and developing new reatments," said Cairns.

ALS is a condition that kills motor neurons, the nerve cells that ontrol muscles. This leads to gradually increasing paralysis and auses death over a course of several years. Almost 5 to 10 pct f all ALS cases are inherited and the rest are sporadic.

Researchers linked an inherited form of ALS to mutations in the ene for a protein called superoxide dismutase-1 (SOD1) in 1993. fter that, many thought altering the SOD1 gene's function was he most promising way to model and understand sporadic ALS.

"That has all been turned upside down in the last two years, hough. In that time, abnormal TDP-43 deposits have been dentified in sporadic ALS cases and in some inherited forms of LS that don't involve a SOD1 mutation," said Cairns.

TDP-43 is an influential regulator of messenger RNA splicing, the rocess that edits protein-building instructions from DNA to llow the proteins to be built properly. TDP-43 abnormalities in LS patients include altered folding and a chemical change known s phosphorylation, both of which can drastically alter the rotein's function. Thus, many researchers have been looking for case where a mutation in the TDP-43 gene was linked to nherited disease.

The current study is the first to tentatively establish such a ink. The researchers found that every member of a family ffected by an inherited form of ALS had a particular mutation in DP-43.

Later, they examined 1,505 people not related to the family and naffected by ALS. No examples of the same mutation were found in his second search.

Scientists need further evidence to confirm that the mutation is ausing ALS, as the family they studied is small. Work is going n to introduce the mutated human TDP-43 gene they identified in he family into a transgenic mouse model and the researchers are oping that the mouse will generate a model for ALS-like athology.

If the link gets affirmed, the researchers will start to trace he effects of the mutation on genes whose splicing is regulated y TDP-43, working to identify key links in the chain reaction hat leads to motor neuron death. These links may become new argets for pharmaceutical treatments.

This may further explain other neurodegenerative disorders. ccording to the researchers, abnormal TDP-43 has been found in atients with frontotemporal dementia, the second most common ause of early-onset dementia after Alzheimer's disease.

"As our understanding of these diseases progresses, we're tarting to see common elements. This protein may allow us to ink together a number of important disease entities and pinpoint ew targets for therapeutic intervention," said Alison M. Goate, ne of the authors of the study.

The study appears in the recent issue of Annals of Neurology. ANI)

ANI

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