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Fused in Sarcoma (FUS)

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Using loss‐of‐heterozygosity mapping in a consanguineous family, variants in a region of chromosome 16 were identified to be linked with ALS [33]. Simultaneously, a separate group found fused in sarcoma (FUS) variants segregating dominantly in several pedigrees after screening a similar linkage region [34]. Protein‐altering variants have been observed across the FUS coding sequence, but the most penetrant variants (not in unaffected controls) are clustered in the nuclear localization signal (NLS) domain of the last exon [17]. FUS variants have been linked to strongly penetrant and dominantly inherited forms of ALS. Indeed, variants in FUS have been consistently associated with earlier onset and even juvenile cases of ALS, with age at onset generally below the disease average [35]. While this is a rare cause of both familial and sporadic ALS (approximately 4% of familial ALS and less than 1% of sporadic [4]), the discovery of another aggregating RNA‐binding protein in ALS strengthened the themes of protein aggregation, RNA metabolism, and nuclear trafficking [17].

FUS and TDP‐43 are similar in that they localize in the nucleus under normal conditions, regulate splicing of pre‐mRNA, transport transcripts from the nucleus, and form cytoplasmic aggregates in the presence of specific ALS‐associated variants [36, 37]. However, FUS is also a transcription factor, binding to open chromatin to regulate transcription of RNA [38]. FUS directly binds to RNA on long introns but also interacts with splicing machinery to affect RNA processing indirectly [37]. FUS has a different RNA sequence recognition motif compared to TDP‐43 and does not bind the same set of transcripts [36]. Further, FUS also binds a specific secondary structure of RNA in addition to its sequence motif [35]. Cytoplasmic FUS aggregates might suggest a loss of these specific RNA binding functions as FUS is sequestered [39], and it is unclear whether FUS aggregates are toxic or an indication of lowered FUS activity.

Spectrums of Amyotrophic Lateral Sclerosis

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