Transcriptional and Post-Transcriptional Regulation of SPAST, the Gene Most Frequently Mutated in Hereditary Spastic Paraplegia

Abstract

Hereditary spastic paraplegias (HSPs) comprise a group of neurodegenerative disorders that are characterized by progressive spasticity of the lower extremities, due to axonal degeneration in the corticospinal motor tracts. HSPs are genetically heterogeneous and show autosomal dominant inheritance in ∼70–80% of cases, with additional cases being recessive or X-linked. The most common type of HSP is SPG4 with mutations in the SPAST gene, encoding spastin, which occurs in 40% of dominantly inherited cases and in ∼10% of sporadic cases. Both loss-of-function and dominant-negative mutation mechanisms have been described for SPG4, suggesting that precise or stoichiometric levels of spastin are necessary for biological function. Therefore, we hypothesized that regulatory mechanisms controlling expression of SPAST are important determinants of spastin biology, and if altered, could contribute to the development and progression of the disease. To examine the transcriptional and post-transcriptional regulation of SPAST, we used molecular phylogenetic methods to identify conserved sequences for putative transcription factor binding sites and miRNA targeting motifs in the SPAST promoter and 3′-UTR, respectively. By a variety of molecular methods, we demonstrate that SPAST transcription is positively regulated by NRF1 and SOX11. Furthermore, we show that miR-96 and miR-182 negatively regulate SPAST by effects on mRNA stability and protein level. These transcriptional and miRNA regulatory mechanisms provide new functional targets for mutation screening and therapeutic targeting in HSP.

New perspectives on the development of muscle contractures following central motor lesions

“…Recent studies have demonstrated that miRNAs may play critical roles in diseases affecting skeletal muscle, including hereditary spastic paraplegia (Henson et al . ), muscular dystrophies (Liu & Bassel‐Duby, ), and amyotrophic lateral sclerosis (ALS) (Campos‐Melo et al . ).…”

“…miRNAs influence various biological events, including cell death, differentiation, proliferation and cell growth (Liu & Bassel-Duby, 2015). Recent studies have demonstrated that miRNAs may play critical roles in diseases affecting skeletal muscle, including hereditary spastic paraplegia (Henson et al 2012), muscular dystrophies (Liu & Bassel-Duby, 2015), and amyotrophic lateral sclerosis (ALS) (Campos-Melo et al 2013). Cacchiarelli et al 2010 observed a higher expression of miR-31 in muscle biopsies of DMD patients when compared to healthy muscle.…”

Mutations in the SPAST gene causing hereditary spastic paraplegia are related to global topological alterations in brain functional networks

“…Spastic paraplegia type 4 (SPG4) is caused by mutations in the SPAST gene (located on 2p22.3), which encodes for an enzyme called spastin [ 7 , 8 ]. SPG4 is the most common autosomal-dominant form of HSP, accounting for approximately 40% of familial [ 9 ] and 10% of sporadic [ 10 ] cases.…”

Tau missorting and spastin-induced microtubule disruption in neurodegeneration: Alzheimer Disease and Hereditary Spastic Paraplegia

“…Transcription of spastin was shown to be upregulated by the transcription factors NRF1 and SOX11, whereas miR-96 and miR-182 downregulate both mRNA stability and protein levels of spastin [ 27 ].…”