A variant of the Hspa8 synaptic chaperone modifies disease in a SOD1 mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a relatively common and invariably fatal, paralyzing motor neuron disease for which there are few treatment options. ALS is frequently associated with ubiquitin-positive motor neuronal aggregates, a pathology suggestive of perturbed proteostasis. Indeed, cellular chaperones, which are involved in protein trafficking and degradation often underlie familial ALS.

Muscle: an independent contributor to the neuromuscular spinal muscular atrophy disease phenotype.

Spinal muscular atrophy (SMA) is a pediatric-onset neuromuscular disorder caused by insufficient survival motor neuron (SMN) protein. SMN restorative therapies are now approved for the treatment of SMA; however, they are not curative, likely due to a combination of imperfect treatment timing, inadequate SMN augmentation, and failure to optimally target relevant organs. Here, we consider the implications of imperfect treatment administration, focusing specifically on outcomes for skeletal muscle.

Genome-wide chromatin occupancy of BRDT and gene expression analysis suggest transcriptional partners and specific epigenetic landscapes that regulate gene expression during spermatogenesis.

BRDT, a member of the BET family of double bromodomain-containing proteins, is essential for spermatogenesis in the mouse and has been postulated to be a key regulator of transcription in meiotic and post-meiotic cells. To understand the function of BRDT in these processes, we first characterized the genome-wide distribution of the BRDT binding sites, in particular within gene units, by ChIP-Seq analysis of enriched fractions of pachytene spermatocytes and round spermatids. In both cell types, BRDT binding sites were mainly located in promoters, first exons, and introns of genes.

p300-mediated acetylation of TRF2 is required for maintaining functional telomeres.

The human telomeric protein TRF2 is required to protect chromosome ends by facilitating their organization into the protective capping structure. Post-translational modifications of TRF2 such as phosphorylation, ubiquitination, SUMOylation, methylation and poly(ADP-ribosyl)ation have been shown to play important roles in telomere function. Here we show that TRF2 specifically interacts with the histone acetyltransferase p300, and that p300 acetylates the lysine residue at position 293 of TRF2.

Ubiquitin Ligase RLIM Modulates Telomere Length Homeostasis through a Proteolysis of TRF1.

The telomeric protein TRF1 negatively regulates telomere length by inhibiting telomerase access at the telomere termini, suggesting that the protein level of TRF1 at telomeres is tightly regulated. Regulation of TRF1 protein abundance is essential for proper telomere function and occurs primarily through post-translational modifications of TRF1. Here we describe RLIM, a RING H2 zinc finger protein with intrinsic ubiquitin ligase activity, as a TRF1-interacting protein.