Amyotrophic Lateral Sclerosis Related Antibodies

The GGGGCC (G4C2) hexanucleotide repeat expansion in the open reading frame 72 gene (C9ORF72) on chromosome 9 is the most common genetic cause of ALS. G4C2 repeat expansion in the non-coding region of C9ORF72 is thought to cause ALS via at least one of the following three mechanisms: (1) cytotoxicity mediated by repetitive RNA, (2) cytotoxicity mediated by dipeptide repeat protein (DPR), and (3) haploinsufficiency results in a drop in C9ORF72 functional protein levels.

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TDP-43 is a DNA/RNA-binding protein that is normally found in the nucleus and is encoded by the TARDBP gene. TDP-43 affects a variety of RNA metabolic processes, including mRNA splicing, transport, translation, and microRNA synthesis. TDP-43 is one of the most thoroughly studied pathogenic proteins in ALS. TDP-43 may contribute to the pathogenic process of ALS in two ways: (1) TDP-43's normal role in the nucleus is lost; and (2) the creation of TDP-43 cytoplasmic aggregates contributes to the incidence of ALS via cytotoxic GOF.

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ALS can be caused by FUS (fused in sarcoma/translocated in liposarcoma, FUS/TLS) mutations. More than 50 distinct FUS mutations have been identified in ALS patients to date, with many of them interfering with nuclear localization signals and causing FUS to mislocalize to the cytoplasm. FUS pathogenesis in ALS is comparable to TDP-43 etiology. The first is toxic GOF generated by FUS aggregation, and the second is LOF caused by FUS mislocalization in the cytoplasm and loss of nuclear function.

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