Excitotoxicity and ALS: New therapy targets an old mechanism.

Excitotoxicity-induced cell death in motor neurons is a major therapeutic target for amyotrophic lateral sclerosis (ALS). Yan et al. present a novel compound to specifically disrupt extra-synaptic NMDAR complexes, extending the lifespan of the SOD1 ALS mouse and ameliorating cell death.

Targeting phosphoglycerate kinase 1 with terazosin improves motor neuron phenotypes in multiple models of amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with heterogeneous aetiology and a complex genetic background. Effective therapies are therefore likely to act on convergent pathways such as dysregulated energy metabolism, linked to multiple neurodegenerative diseases including ALS.

Methods: Activity of the glycolysis enzyme phosphoglycerate kinase 1 (PGK1) was increased genetically or pharmacologically using terazosin in zebrafish, mouse and ESC-derived motor neuron models of ALS.

SMN-primed ribosomes modulate the translation of transcripts related to spinal muscular atrophy.

The contribution of ribosome heterogeneity and ribosome-associated proteins to the molecular control of proteomes in health and disease remains unclear. Here, we demonstrate that survival motor neuron (SMN) protein-the loss of which causes the neuromuscular disease spinal muscular atrophy (SMA)-binds to ribosomes and that this interaction is tissue-dependent. SMN-primed ribosomes are preferentially positioned within the first five codons of a set of mRNAs that are enriched for translational enhancer sequences in the 5' untranslated region (UTR) and rare codons at the beginning of their coding sequence.