The results of a new study conducted by a team of researchers from Australia’s University of Wollongong, Macquarie University’s Australian School of Advanced Medicine, and Macquarie University’s Australian School of Advanced Medicine suggest that there may be another mutated gene link to amyotrophic lateral sclerosis, or ALS.
The paper ”CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia” found that Cyclin F (CCNF), a protein coding gene, and its variants were present in family members with a history of ALS and frontotemporal dementia (FTD) as well as sporadically among non-familial subjects. Using both genome-wide linkage analysis and next generation whole-exome sequencing to identify the mutation, CCNF appears with a frequency comparable to FUS (an RNA binding protein) and TDP-43 (a DNA binding protein) mutations.
Role of CCNF
Cyclin F, comprising part of the UPS (ubiquitin-protease system), attaches an ubiquitin to target proteins which cells identify in order to eliminate unwanted proteins in the proteasome. The CCNF mutation interferes with this, causing it to accumulate and gum up the works, potentially explaining why motor neurons and cortical neurons are affected.
The Process
The study first analyzed genome data from a family of which ten members had ALS, and found that all had a chromosome-16 variation, as well as other mutations. While abnormally ubiquitinated proteins are present in those with ALS and FTD, the research found that the mutant cyclin F encoded in CCNF was a potential source of the abnormal ubiquitination and contributed to the accumulation of ubiquitinated proteins.
To validate these results, the researchers scoured the genetic data of hundreds of families with a history of ALS in Japan, Europe, and North America, as well as Australia. What they found were 25 different variants of protein altering mutations in CCNF associated with the disease.
The Implications of the CCNF Study
If this gene mutation is indeed an indicator of ALS or FTD, testing can be performed, allowing affected individuals to take steps to prevent passing it along to their progeny. In addition, in vitro testing may also be performed to identify CCNF thereby allowing parents to take measures to circumvent, or at least delay, its effects.
In addition, because an environmental cause of ALS is becoming increasingly doubtful, it may be that “sporadic” ALS is, in fact, a combination of genetic mutations that clog and damage the motor and cortical neuron pathways that result in ALS/FTD.
