The finding was subsequently replicated by sellectchem independent groups in different populations [47,48]. Only a short period of time has passed since the discovery of the C9ORF72 repeat expansion, but already certain aspects are becoming clear. The pathogenic expansion on chromosome 9p21 is by far the most frequent cause of ALS and FTLD identified to date, being at least twice as common as SOD1 mutations in ALS, and as PGRN mutations in FTLD. The discovery of the hexanucleotide repeat expansion increased the proportion of familial ALS that was explained from one-quarter to nearly two-thirds. It also showed that genetics plays a major role in apparently sporadic ALS and FTLD, thereby unifying the two major forms of the disease: in a large cohort of white Europeans, Americans, and Australians the C9ORF72 repeat was identified in approximately 6% of both sporadic ALS and FTLD cases [49].

Patients with pure ALS, pure FTLD, or ALS-FTLD have 700 to 1,600 repeats that may be up to 10 kb in length, whereas people without these diseases have fewer than 24 repeats [44,45]. But what does C9ORF72 do? The key question among researchers at the moment is ‘what is the normal function of C9ORF72′ and ‘by what cellular mechanism does the pathogenic repeat expansion lead to neurodegeneration?’ C9ORF72 encodes a highly conserved, 481 (full-length) amino acid protein. The protein has no discernable domains, and consequently, little is known about its function. There are three reported splice variants with the pathogenic repeat expansion variably lying within the promoter or first intron of the different transcripts [44,45].

Different mechanisms of disease can be postulated for any of the repeat expansion disorders, including loss of function, gain of function due to abnormal RNA toxicity, or gain of function due to abnormal protein toxicity [50]. At the present time, it is unclear which of these mechanisms is operating in C9ORF72-ALS, and there are conflicting data for each: the location of the repeat directly within the promoter of the long C9ORF72 transcript suggests the possibility that the expansion alters C9ORF72 expression, at least of this isoform. Altered C9ORF72 transcription Drug_discovery is supported by both original Neuron papers, which identified reduced expression of the longer mRNA isoforms in brain [44,45].

On the other hand, most of the autopsy-confirmed mutation carrier patients had TDP-43 inclusions in brain or spinal cord, indicating that abnormal protein accumulation is important, regardless of the initiating cellular mechanism [51,52]. Furthermore, the RNA inclusions reported in the original DeJesus-Hernandez selleck inhibitor et al. paper [44] suggest that toxic RNA species generated from the expansion may be important. So far these initial findings have proven difficult to replicate, perhaps because of the technical difficulties inherent in in situ hybridization [53,54].