Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington's Disease.

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin () gene. We report the design of a series of pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of mRNA transcripts and protein levels.

Genotype and Injury Effect on the Expression of a Novel Hypothalamic Protein Sushi Repeat-Containing Protein X-Linked 2 (SRPX2).

Sushi repeat-containing protein X-linked 2 (SRPX2) is a novel hypothalamic protein and a ligand of the urokinase-type plasminogen activator receptor (uPAR), which is essential for proteolysis of extracellular matrix and tissue remodeling after an insult to the brain. However, little is known about regulation of SRPX2. Our objective was to investigate if SRPX2 expression is altered by (i) the deficiency of uPAR or uPA (urokinase-type plasminogen activator), and (ii) traumatic brain injury (TBI).

Deficiency of urokinase-type plasminogen activator and its receptor affects social behavior and increases seizure susceptibility.

Extracellular proteolysis initiated by the binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR) regulates the development of inhibitory neuronal circuits in the cerebral cortex and tissue remodeling after epileptogenic brain injury. To study the function of different components of the uPA-uPAR system on behavior and epileptogenesis, and to complement our previous studies on naïve and injured mice deficient in the uPA-encoding gene Plau or the uPAR-encoding gene Plaur, we analyzed the behavioral phenotype, seizure susceptibility, and perineuronal nets surrounding parvalbumin-positive inhibitory interneurons in Plau and Plaur (double knockout dKO) mice. In a climbing test, dKO mice showed reduced interest towards the environment as compared with Wt mice (p < 0.

Sushi repeat-containing protein X-linked 2: A novel phylogenetically conserved hypothalamo-pituitary protein.

Sushi repeat-containing protein X-linked 2 (SRPX2) is a novel protein associated with language development, synaptic plasticity, tissue remodeling, and angiogenesis. We investigated the expression and spatial localization of SRPX2 in normal mouse, rat, monkey, and human brain using in situ hybridization and immunohistochemistry. Antibody specificity was determined using in vitro siRNA based silencing of SRPX2.

Epileptogenesis after traumatic brain injury in Plaur-deficient mice.

Binding of the extracellular matrix proteinase urokinase-type plasminogen activator (uPA) to its receptor, uPAR, regulates tissue remodeling during development and after injury in different organs, including the brain. Accordingly, mutations in the Plaur gene, which encodes uPAR, have been linked to language deficits, autism, and epilepsy, both in mouse and human. Whether uPAR deficiency modulates epileptogenesis and comorbidogenesis after brain injury, however, is unknown.