Scientists have found that mutations in the ubiquilin-2 gene, as well as abnormal accumulation of the ubiquilin-2 protein, can cause amyotrophic lateral sclerosis (ALS) and ALS/dementia.
"We've defined a new pathology in ALS patients involving ubiquilin-2 protein, which has never been seen before," senior study author Teepu Siddique, MD, a neuroscientist at Northwestern's Feinberg School of Medicine in Chicago, Illinois, noted in an interview with Medscape Medical News. "When we extend these pathologic studies to all of ALS and ALS/dementia, we see the same pathology in the brains and spinal cords of these patients," he added.
Dr. Teepu Siddique
"Not only have we defined a new cause that seems to be operative in all of ALS, but also we have now shown that the most likely mechanism is a problem with disposal of misfolded or damaged proteins," Dr. Siddique added.
The discovery opens a whole new field for finding an effective treatment for the disease, Dr. Siddique noted in a prepared statement. "We can now test for drugs that would regulate this protein pathway or optimize it, so it functions as it should in a normal state."
The research was published online August 21 in Nature.
Faulty Recycling System
Between 5% and 10% of ALS cases are familial, and previously described mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein (TARDBP, also known as TDP43), and fused in sarcoma (FUS, also known as translocated in liposarcoma (TLS) account for some 30% of classic familial ALS, the researchers note in their report. The causes of the remaining cases of familial ALS and of the vast majority of sporadic ALS are unknown.
Despite extensive studies of previously identified ALS-causing genes, the pathogenic mechanism underlying motor-neuron degeneration in ALS "remains largely obscure," they note. Dementia, usually of the frontotemporal lobar type, may occur in some ALS cases, but it's unclear whether ALS and dementia share common etiology and pathogenesis in ALS/dementia."
In these functional analyses, the scientists found that a number of mutations in the ubiquilin-2 gene, which is on the X chromosome, can cause an X-linked form of juvenile and adult-onset familial ALS, as well as ALS with dementia.
They found novel ubiquilin-2 pathology in the spinal cords of ALS cases and in the brains of ALS/dementia patients whether or not there was a mutation present.
The ubiquilin-2 protein plays a role in cellular maintenance. It recycles damaged or misfolded proteins in motor and cortical neurons. In people with ALS, it appears that this key function breaks down, leading to the accumulation of damaged proteins in motor neurons in the spinal cord and cortical and hippocampal neurons in the brain.
In a statement, Han-Xiang Deng, MD, first author on the Nature paper and associate professor of neurology at the Feinberg School, notes that faulty protein degradation in ALS "has been suspected, but there was little direct evidence before this study."
New Research Avenue
Although several genes linked to ALS have been identified, until now, the pathogenic mechanisms underlying motor neuron degeneration in ALS have remained largely obscure, preventing development of effective therapeutic approaches.
The scientists say the exact function of ubiquilin-2 is not well understood. However, there is increasing evidence that ubiquilins, together with their interactions with other proteins, may play a role in several neurodegenerative disorders, including Alzheimer's disease, frontotemporal dementia, and Parkinson's disease.
"The identification of a new gene linked to familial ALS known to be involved in protein handling of the cell will open up a new avenue of research and bring us closer to understanding this process and what goes wrong in the disease," ALS Association Chief Scientist Lucie Bruijn, PhD, commented in a statement posted on the association's Web page.
"We look forward to follow-on studies that bring us closer to effective therapy for the disease," Dr. Bruijn added.
