Neuronal Transcriptional Regulatory Mechanisms, Spastic Paraplegia

Hereditary spastic paraplegias (HSP) are a set of clinically diverse neurodegenerative disorders characterized primarily by progressive spasticity in the lower limbs due to axonal degeneration of the corticospinal tract (CST).

HSP may be pure or complex, the latter found with additional neurological features such as mental retardation and epilepsy. Dominant inheritance accounts for approximately 70 percent of HSP and mutations in one gene, SPAST (SPG4), are the cause of over 40 percent of these cases. Nevertheless, to date, 45 assigned gene symbols exist for autosomal dominant and recessive, and X-linked, gene loci that are chromosomally linked to HSP pathogenesis but the etiological gene mutations have been identified to date for only 17 or 18 of these.

Known spastic paraplegia genes (SPG) encode proteins involved in a multitude of distinct biochemical pathways, attesting to the diverse molecular mechanisms that can affect function and trafficking in long axons, but making selection of new candidate genes difficult. This research hypothesizes that many SPG loci are co-regulated in order to express the encoded functions in proper CST spatiotemporal patterns.

By bioinformatics analyses of human genome sequences this research found that the promoters or 5’ regulatory regions for 9 of 16 autosomal HSP genes have one or more binding site motifs for the transcription factor (TF) Nuclear Respiratory Factor-1 (NRF1), including SPG4, SPG5, SPG6, SPG7, SPG8, SPG11, SPG13, SPG20 and putative SPG33. These sites are evolutionary conserved in all or most eutherian mammals and for some sites, in the marsupial and monotreme. Remarkably, the mammalian SPG7 promoter is comprised of an array of one to six NRF1 sites and no other conserved TF motifs. Researchers confirmed that NRF1 binds in vivo at these regulatory elements using chromatin immunoprecipitation with human and mouse neuroblastoma cell lines. Additionally, siRNA targeting NRF1 mRNA downregulates expression of these SPG loci as well as luciferase reporter constructs for minimal promoters of the SPG4 and SPG6 loci. Since NRF1 sites occur in the promoters of approximately 5 to 6 percent of genes across the genome but these are found in approximately 55 percent of SPG promoters, this research suggests that NRF1 coordinates a gene regulatory network (GRN) comprising many of the genes involved in HSP pathogenesis. Further, this research suggests that identification of NRF1 target genes, and other TFs within the GRN, within large chromosomal domains linked to uncloned HSP loci will improve selection of candidate genes for mutation studies.

Principal Investigator
Robert Nicholls, PhD

Last Update
August 14, 2010
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Last Update
August 14, 2010