Discovery points to common cellular deficiency in motor neuron disorder

February 27, 2009

WORCESTER, Mass. — Researchers at the University of Massachusetts Medical School (UMMS) have discovered a new gene whose mutations cause familial amyotrophic lateral sclerosis (ALS), a fatal neurological disorder. Discovery of the FUS/TLS gene mutation, which is estimated to account for 5 percent of inherited ALS cases, is described in the February 27, 2009 issue of Science.

“This discovery discloses new types of molecular defects that kill motor neurons and at the same time implicates defective pathways previously identified in other genetic forms of ALS,” said Robert H. Brown Jr., MD, DPhil, the senior investigator of the study and chair and professor of neurology at UMMS. “Understanding the mechanisms that trigger motor neuron death leads to new cellular models of ALS and ultimately accelerates the search for a treatment for this devastating disease.”

ALS is a progressive, neurodegenerative disorder affecting the motor neurons in the central nervous system. As motor neurons die, the brain’s ability to send signals to the body’s muscles is compromised. This leads to loss of voluntary muscle movement, paralysis and eventually death from respiratory failure. The cause of most cases of ALS is not known. Approximately 10 percent of cases are inherited. In 1993, a team of researchers led by Dr. Brown discovered the first gene linked to familial ALS, a protein anti-oxidant known as superoxide dismutase, or SOD1.

The current Science study details the discovery of the FUS/TLS gene mutation among four members of a family from a small Cape Verde island. The familial relationship between the patients’ grandparents suggested that the disorder was a result of a recessive gene inherited from both parents. Deep sequencing of several candidate genes on chromosome 16, which has been linked to ALS in previous studies, revealed a single mutation in the FUS/TLS gene on both copies of chromosome 16 in the affected family members. Three asymptomatic family members from the Cape Verde family also had two mutated copies of FUS/TLS but had not reached the age of onset of ALS. Several unaffected family members had only a single copy of the FUS/TLS mutation. No mutations in the FUS/TLS gene were found in a control group of 1,446 North American individuals.

Sequencing of the FUS/TLS gene in two other families, previously thought to have an ALS-associated gene on chromosome 16, disclosed additional mutations. Analysis of 81 other unrelated familial ALS occurrences revealed 13 different FUS/TLS gene mutations among 17 families. No mutations were found in the 293 sporadic, non-familial ALS cases sampled or the 1,446 control cases.

While it is not certain how the mutation of the FUS/TLS gene causes ALS, the cellular functions it controls within the motor neurons are remarkably similar to those found in other gene mutations known to cause ALS. The FUS/TLS protein plays a number of roles in the neuron cell, one of which is to bind and transport RNA, regulating the processes whereby RNA leads to protein synthesis. In healthy neuron cells, FUS/TLS protein is located predominately in the cell nucleus. Samples from patients with the FUS/TLS mutation show a concentration of the FUS/TLS protein in the cytoplasm of the cell. This same build-up of proteins in the neurons’ cytoplasm is found in ALS patients with a mutation of the TDP43 gene – which also binds to RNA – suggesting a potential common pathogenic mechanism in ALS cases caused by defects in either FUS/TLS or TDP43.

“The implication is that disturbance of RNA transport and function could play a role in the biology of this disease; this is particularly exciting for us at UMMS because we have outstanding scientists here in the field of RNA biology,” said Brown.

A team at King’s College London (KCL), led by Christopher Shaw, MD, DPhil verified the findings made by Dr. Brown and his colleagues. The KCL team reported FUS/TLS mutations in eight apparently unrelated families and went on to characterize the effect of the mutations in cultured cells. They also identified deposits of FUS/TLS protein in motor neurons of three patients with FUS/TLS mutations, deposits absent from patients with SOD1 mutations or sporadic ALS.

Lucie Bruijn, PhD, senior vice president of research and development for the ALS Association, said “These findings will open up a completely new avenue of investigation with the potential of developing more promising therapies for ALS.”

The study was supported by grants from the National Institutes of Health, the Angel Fund, the ALS Therapy Alliance, the ALS Association, Project ALS, the Al-Athel ALS Research Foundation and the Pierre de Bourgknecht ALS Research Foundation. Brown and Thomas Kwiatkowski, MD, PhD, lead author of the Science study and a researcher at the Day Neuromuscular Research Laboratory in the MassGeneral Institute for Neurodegenerative Disease, have applied for a patent covering FUS/TLS mutations in ALS. Brown is also a co-founder of AviTx Inc., a company working to develop ALS therapies.

About the University of Massachusetts Medical School
The University of Massachusetts Medical School has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research. The Medical School attracts more than $200 million in research funding annually, 80 percent of which comes from federal funding sources. The work of UMMS researcher Craig Mello, PhD, an investigator of the prestigious Howard Hughes Medical Institute (HHMI), and his colleague Andrew Fire, PhD, then of the Carnegie Institution of Washington, toward the discovery of RNA interference was awarded the 2006 Nobel Prize in Physiology or Medicine and has spawned a new and promising field of research, the global impact of which may prove astounding. UMMS is the academic partner of UMass Memorial Health Care, the largest health care provider in Central Massachusetts.