Following a Northwestern Medicine breakthrough that identified a common converging point for all forms of amyotrophic lateral sclerosis (ALS and Lou Gehrig’s disease), a finding from the same scientists explains why brain and spinal cord cells degenerate in the fatal disease.

Less than three months ago, Northwestern research found that the recycling system for cells in the brain and spinal cord was broken in people with ALS and one mutated gene had a key role. Like a loafing worker, it wasn’t doing its job to recycle damaged cells.  Now, scientists have discovered a second faulty gene—a new loafing worker—in the same recycling pathway.

“Now that we have two bad players, it shines more light on this broken pathway,” says Teepu Siddique, MD, the Davee Department of Neurology and Clinical Neurosciences at Northwestern’s Feinberg School professor. “This gives us a clear target to develop drug therapies to try to fix this problem. It strengthens our belief that this broken system is at the heart of ALS.”

The “bad player,” is sequestosome1, and the previously identified mutated gene is ubiquilin2. Because these two genes aren’t doing their jobs to recycle damaged proteins, those proteins—as well as sequestosome1 and ubiquilin2—accumulate abnormally in the motor neurons in the spinal cord and cortical and hippocampal neurons in the brain. The protein accumulations resemble twisted skeins of yarn (a characteristic of ALS) and cause the degeneration of the neurons.

In the study, sequestosome1 genetic mutations were identified in 546 ALS patients; 340 with familial, an inherited form of the disease, and 206 with sporadic, a non-inherited form of the disease.

About 90% of ALS is sporadic and 10% is familial. Mutations in about 10 genes, including SOD1 and ALSIN, account for about 30% of classic familial ALS, notes Faisal Fecto, MD, a PhD candidate in neuroscience at Feinberg.

The discovery of the breakdown in protein recycling may also have a wider role in other neurodegenerative diseases, particularly the dementias. These include Alzheimer’s disease and frontotemporal dementia as well as Parkinson’s disease, all of which are characterized by aggregations of proteins, Siddique says. The removal of damaged or misfolded proteins is critical for optimal cell functioning, he notes.

The finding is reported in Archives of Neurology.

Release Date: Nov. 21, 2011
Source: Northwestern University