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Jul 23
2020

Research Byte: ALS mutations in UBQLN2 linked to an acidification defect in protein recycling

Research Bytes
Packard scientist Mervyn Monteiro showed that ALS-linked mutations in UBQLN2 interferes with autophagy by blocking an acidification step critical for the process.

Mutations in the gene UBQLN2 are linked to ALS and frontotemporal dementia (FTD). The UBQLN2 gene plays a major role in protein degradation and recycling, assisting in both proteasome and autophagy disposal, defects in which are frequently linked to ALS/FTD. What scientists didn’t know was how mutations interfered with the normal job of UBQLN2, and how this then led to disease. In a new study in the Proceedings of the National Academy of Sciences, Packard scientist Mervyn Monteiro, a neuroscientist at the University of Maryland Medical School, together with colleagues across the globe, showed that ALS-linked mutations in UBQLN2 interferes with autophagy by blocking an acidification step critical for the process.

When scientists examine nervous system tissue from people who have died from neurodegenerative diseases, they frequently find a build-up of proteins tagged with ubiquitin. The ubiquitin tag serves to mark proteins for clearance, and its accumulation in neurodegenerative disease indicates a dysregulation of the clearance systems. Cells use two main pathways to clear the tagged proteins: the proteasome, which degrades soluble proteins, and autophagy, which degrades larger protein aggregates and cellular organelles.

When the investigators examined the brains and spinal cord tissue of the UBQLN2 mouse model of ALS/FTD that the Monteiro group had generated, they found mis-accumulation of markers of autophagy, many of which physically associated with dense clumps of UBQLN2, something the researchers also saw in brain tissue from people who had died from UBQLN2 ALS/FTD. Monteiro and colleagues concluded that these abnormalities were indicative of defects in autophagy.

To understand how UBQLN2 functions in autophagy, they inactivated the UBQLN2 gene in human cells and found it stalled autophagy. Reintroduction of the normal UBQLN2 protein restarted the process. However, reintroduction of UBQLN2 proteins with ALS mutations were ineffective in restarting autophagy, indicating the mutants had lost their normal function. Further experiments showed that the UBQLN2 protein directly participates in autophagy via its presence in autophagosomes, the organelles in the cell where molecules are packaged prior to degradation. In the absence of UBQLN2, the authors found autophagosomes were unable to turn acidic, a pH transition that is critical to initiate protein breakdown. The authors found that the lack of acidification stemmed from a reduction of a piece of the proton pump that makes the interior of the autophagosome acidic. They found the synthesis of the missing pump component was regulated by UBQLN2, and that the ALS mutants could not make sufficient levels of it.

Taken together, these new findings suggest restoring the acidification defect in autophagy might provide a novel therapeutic target for ALS/FTD.

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