How Ubiquilins Influence ALS

A new study improves our understanding of how amyotrophic lateral sclerosis (ALS) develops. The study, which appeared today in the journal Nature Cell Biology, suggests potential new therapeutic strategies for ALS and frontotemporal dementia.

A common feature of this progressive neuromuscular condition is an imbalance between the synthesis and degradation of proteins within cells. When this balance is tipped, excess waste builds up in cells and disease develops. In the present study, researchers discovered that mutated ubiquilin proteins interrupt protein degradation by failing to regulate lysosomes.

To understand the link between ubiquilin and progressive neurodegeneration, the researchers conducted initial experiments in fruit flies lacking the gene ubiquilin. These mutant flies showed signs of progressive age-dependent neurodegeneration, such as impaired neuronal function, death of neurons, and increased accumulation of aberrant lysosomes.

Previous studies have shown that ubiquilins play a key role in the degradation of dysfunctional proteins at the proteasome. However, defects in the proteasome clearing process alone could not explain the dramatic loss of neurons that the researchers observed in these mutants. Further studies showed that autophagy, another process involved in discarding excess or dysfunctional proteins, also appeared to be defective in ubiquilin mutants.

“This suggested that a combined malfunction in the proteasomal and autophagic clearance mechanisms was responsible for the massive buildup of dysfunctional proteins and eventual death of these neurons,” says senior author Hugo Bellen of Baylor College of Medicine.

Autophagy is a multistep process. First, vesicles called autophagosomes engulf damaged proteins. Then, autophagosomes fuse with lysosomes—vesicles whose acidic environment activates enzymes that degrade cellular waste. Therefore, the researchers next set out to pinpoint which step of autophagy was being affected in the absence of ubiquilin.

“To our surprise, we found that in these mutant flies, the lysosomes were not acidified, which meant that enzymes that digest cellular garbage could not be activated, leading to waste accumulation,” says first author Mümine Şentürk.

When the researchers fed acidic nanoparticles to the flies to restore the acidic environment inside the lysosomes, clearance of accumulated trash and the normal flow of the process improved.

“Interestingly, we observed the same lysosomal degradation defects in human neuronal cells lacking ubiquilins, suggesting an evolutionarily conserved role for these proteins in regulating the clearance pathways,” Bellen explains. “Further studies are needed to test whether acidic nanoparticles also can promote the survival of neurons in the brains of intact mammals.”