IBM Research: Doubts about Tau

Abnormal accumulation of a protein called "tau" has been considered by many to contribute to muscle degeneration in inclusion-body myositis (IBM). But recently, MDA grantee Steven Greenberg and colleagues at Brigham and Women's Hospital and Harvard Medical School in Boston have cast doubt on this purported disease mechanism and say it's too early to develop drugs for IBM based on it.

Greenberg, with Mohammad Salajegheh, also an MDA grantee, and other colleagues, published the new findings online July 22, 2009, in Muscle & Nerve.

About IBM

IBM mainly affects men ages 50 and older, but also can affect women. It involves inflammation and degeneration of muscle tissue. Although there are genetic forms, the cause of the vast majority of cases is unclear. The disease usually isn't treatable, although some patients have responded to medications, such as prednisone, used to treat other forms of myositis.

Under the microscope, IBM-affected muscle fibers show bubblelike spaces (vacuoles) containing clumps of protein (inclusion bodies), as well as invasion by inflammatory cells from the immune system.

MDA grantee Valerie Askanas at the University of Southern California in Los Angeles is a proponent of the hypothesis that muscle aging, with accumulations of abnormal tau and other proteins, are at the root of this disease.

Greenberg believes there is currently no understanding of how muscle is injured in IBM.

normal muscle IBM-affected muscle
In inclusion-body myositis, bubblelike spaces called vacuoles and clumps of proteins form, while inflammatory cells invade the muscle tissue.

About tau

In the brain, tau (rhymes with “now”) protein with too many phosphate molecules attached ("hyperphosphorylated" tau) has been implicated as a cause of Alzheimer's disease and other neurodegenerative conditions, such as frontotemporal dementia. In these diseases, hyperphosphorylated tau protein molecules stick to each other, causing tangles that interfere with brain function.

In IBM, it’s been hypothesized that hyperphosphorylated tau accumulates and forms tangles in muscle fibers, leading to muscle loss and weakness.

About the new findings

The Boston investigators say the tests now used to detect tau, which involve immune-system proteins that act as molecular "magnets" and stick to targeted proteins, actually detect a different protein, called neurofilament H.

They say that nuclei in muscle fibers normally contain phosphorylated proteins, and that these proteins have been misinterpreted as hyperphosphorylated tau.

Meaning for patients

The researchers say they "have concern regarding the rationale for therapeutic development of compounds that target tau metabolism in patients with IBM," such as an ongoing trial of lithium in this disease. They say the tau hypothesis is wrong and that research should proceed along different tracks.

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