A mammoth team of researchers has uncovered a common biological pathway underlying multiple forms of amyotrophic lateral sclerosis, better known as Lou Gehrig's disease, raising hopes of a new target for therapy.
Mutations in a single gene known as UBQLN2 cause hereditary forms of ALS and ALS with dementia, likely through defective degradation of abnormal protein clumps, according to a research letter published online in Nature.
Even patients without the UBQLN2 mutation had features of the disrupted pathway, suggesting that it is a "common pathological feature in a wide spectrum of ALS and ALS/dementia," according to Dr. Teepu Siddique of Northwestern University in Chicago and coauthors.
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"These data provide robust evidence for an impairment of protein turnover in the pathogenesis of ALS and ALS/dementia, and possibly other neurodegenerative disorders, as well," they added. "These pathways should provide novel molecular targets for the design of rational therapies for these disorders."
ALS is usually sporadic, meaning of unknown origin. But up to 10 percent of cases run in familes. Several mutations have been identified, accounting for roughly 30 percent of hereditary ALS. But the cause of the remaining cases remain unknown, the authors wrote.
The UBQLN2 mutation, which results in a defective protein called ubiquilin 2, was discovered in a five-generation family affected by Lou Gehrig's disease. Initially, investigators identified 206 genes of interest, 41 of which were considered relevant to the disease.
"The exact function of ubiquilin 2 is not well understood," the authors noted. "However, there is increasing evidence that ubiquilins, together with their interactions with other proteins, may be involved in neurodegenerative disorders."
Siddique and colleagues then searched for additional UBQLN2 mutations in 188 members of other families with a history of ALS or ALS with dementia. The work led to identification of four additional mutations, none of which was present in a mutation database or in 928 control samples.
The researchers then examined tissue from ALS patients for the presence of ubiquilin 2 in clumps of protein building up inside dying neurons -- a hallmark of ALS. They found ubiquilin 2 in those clumps in both brain and spinal-cord tissue.
To determine whether ubiquilin 2 is involved in other forms of ALS, the authors examined autopsy specimens from 47 patients, including those with sporadic and familial forms of the disease. They found ubiquilin 2-positive clumps in all ALS cases, indicating that it is a common component of protein aggregates of a wide variety of ALS.
"These data provide robust evidence for an impairment of protein turnover in the pathogenesis of ALS and ALS/dementia, and possibly in other neurodegenerative disorders as well," the authors stated. "Further elucidation of these processes may be central to the understanding of pathogenic pathways. These pathways should provide novel molecular targets for the design of rational therapies for these disorders."