BioWorld International Correspondent

LONDON - Genetic analysis of two families with a rare neurodegenerative disease, one from England and one from Pakistan, has allowed researchers to identify the mutation that causes their condition, which is a type of spinocerebellar ataxia.

The gene concerned functions in a pathway that is known to be linked to Alzheimer's disease and frontal dementia. Information from the discovery could help to direct work aimed at identifying therapies for these common types of dementia.

Henry Houlden, senior lecturer and consultant neurologist at the Institute of Neurology and the National Hospital for Neurology and Neurosurgery in London, told BioWorld International: "This gene could turn out to be a drug target. It will be important to find out if, by modulating its activity, we can influence the pathological changes in the brain and the cognition of patients with dementia."

The find is particularly interesting, he added, because the mutation occurs in a gene whose product modifies the protein called tau, which builds up in the brains of people with Alzheimer's disease.

It now will be possible to offer screening, genetic counseling and prenatal diagnosis to the two families that took part in the study, as well as other individuals with the same disease, Houlden said.

An account of the study appears in the Nov. 25, 2007, issue of Nature Genetics, in a paper titled: "Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11."

Houlden and his colleagues previously had identified mutations in genes encoding the proteins beta-amyloid and tau in people with dementia. Sifting through the large database of people with a range of neurodegenerative disorders held at the Institute of Neurology, they focused in on two families with a condition called spinocerebellar ataxia type 11.

One of the families is from Devon, in Southwest England, and has more than 30 affected members. The other, from Pakistan, also has many affected members but only a few have been examined because most still live in Pakistan.

Houlden said: "We were lucky enough to have a sample of brain tissue from a member of the Devon family, and this showed unusual abnormalities in the deposition of tau, which is a component of the neurofibrillary tangles that are commonly deposited in the brain in Alzheimer's disease and frontal dementia. We therefore realized that this type of ataxia could be important to neurodegeneration as a whole, and we put in a major effort to identify the gene."

Patients with spinocerebellar ataxia type 11 typically suffer problems in walking by their teens or 20s, followed by the onset of abnormal jerky eye movements that make it difficult to read, write or drive, with later onset of clumsiness in the arms, and stiffness in the arms and legs. They do not, however, suffer from dementia or memory loss.

About eight years ago, the team managed to localize an area of the genome containing the gene responsible for spinocerebellar ataxia type 11. More recently, as reported in Nature Genetics, they began to sequence all the genes in that region.

"We found a mutation in the tau tuberculin kinase 2 gene, or TTBK2," Houlden said. "All the affected individuals in the pedigrees we were studying have this abnormality, and we have screened many unaffected controls and none of them have the abnormality."

The team went on to study the function of TTBK2, and have shown that normally it phosphorylates tau. "We know that the gene we identified causes phosphorylation of tau in certain places, and we see deposition of tau in the brain tissue of the patient with the disease," Houlden said. "The brain tissue from the affected patient from the Devon family has been extremely valuable in our work and shows how important it is to encourage patients to help in this way after they die."

No one really knows whether the deposition of tau in patients with Alzheimer's disease is the cause of the dementia, or whether the deposited proteins are a by-product of the disease. "Our study sheds an interesting light on this debate," Houlden said, "because you would expect memory problems if tau was a crucial component of the disease, and yet our patients do not suffer from any memory problems that we can detect."

It will be interesting to use cell culture animal models of dementia, Houlden suggested, to investigate how changing the way in which tau is phosphorylated could influence the deposition of tau, and how drugs that target tau kinases influence the severity of dementia.

The Institute of Neurology team plans to search for mutations in the same gene in people with other types of neurodegenerative disease, and analyze new ataxia families that could have this defect. "We also want to find out, using cell culture models, if abnormal phosphorylation of tau caused by this mutation causes cell death," Houlden said.