"Mutations in the Cu/Zn-superoxide dismutase (SOD-1) gene are responsible for a familial form of the motor neuron disease, amyotrophic lateral sclerosis (fALS). Aggregation of mutant SOD1 and formation of cytoplasmic inclusions are pathological hallmarks of the disease in patients and in transgenic mouse models of fALS, and their occurrence suggests overload of proteolytic and protein chaperoning pathways. We studied proteasomal function in transgenic mice over-expressing human SOD-1 carrying the fALS-related mutation G93A (SOD1 G93A). Reduction in proteasomal activities in the lumbar spinal cord (containing vulnerable motor nuclei), but not thoracic spinal cord (less affected area) of pre-symptomatic SOD1G93A transgenic mice relative to non-transgenic littermates and SOD-1WT transgenic mice was measured early in disease pathogenesis. In addition, there was reduction of a subunits of the 20S proteasome in lumbar spinal motor neurons relative to the surrounding neuropil with disease progression. Decreased proteasome activity in lumbar spinal cord corresponded with reduced levels of beta3 (non-catalytic) and beta5 (chymotrypsin-like activity) subunits of the 20S proteasome, despite normal levels of 20Sa subunits in the tissue as a whole. Even though levels of beta3 and beta5 were decreased, they were incorporated into 20S and 26S proteasome complexes as determined by native gel electrophoresis. Levels of beta3 and beta5 mRNA were not decreased in lumbar spinal cord of SOD1 G93A transgenic mice prior to onset of symptoms, indicating unimpaired transcription and mRNA stability. Nor was there evidence that mutant SOD1 inhibited the proteasome by remaining associated with and blocking proteasomes. The relevance of findings in this mouse model of fALS to sporadic ALS was investigated by measuring proteasome activities and expression of proteasomal subunits in autopsy tissue from sporadic ALS patients As in fALS mice, proteasome activity was reduced in extracts of an affected region of spinal cord from ALS patients as compared to controls, whereas the proteasome activity in cerebellar tissue from these patients was not affected. This impairment was coupled with a decrease of 20S beta5 and 19S5a protein levels in spinal cord tissue suggesting that proteasome function is compromised in both familial and sporadic forms of ALS." --

Biomolecular condensation underlies the biogenesis of an expanding array of membraneless assemblies, including stress granules (SGs) which form under a variety of cellular stresses. Advances have been made in understanding the molecular grammar that dictates the behavior of a few key scaffold proteins that make up these phases but how the partitioning of hundreds of other SG proteins is regulated remains largely unresolved. While investigating the rules that govern the condensation of ataxin-2, a SG protein implicated in neurodegenerative disease, we unexpectedly identified a short 14aa sequence that acts as an ataxin-2 condensation switch and is conserved across the eukaryote lineage. We identify poly(A)-binding proteins as unconventional RNA-dependent chaperones that control this regulatory switch. Our results uncover a hierarchy of cis and trans interactions that fine-tune ataxin-2 condensation and reveal a new molecular function for ancient poly(A)-binding proteins as emulsifiers of biomolecular condensate proteins. These findings may inspire novel approaches to therapeutically target aberrant phases in disease.