Researchers at two Scottish institutions have identified a new player in the crucial task of removing protein aggregates from the brain — an otherwise flawed process in Parkinson’s and other neurodegenerative diseases.
The new insights into the molecular processes that contribute to protein aggregates that might some day be therapeutically targeted were recently published in the journal Cell under the title “UBQLN2 Mediates Autophagy-Independent Protein Aggregate Clearance by the Proteasome.”
The research teams from the University of Glasgow and the University of Dundee homed in on a gene called UBQNL2. Scientists already knew that mutations in the gene cause inherited cases of the motor neuron disease amyotrophic lateral sclerosis (ALS), but they did not have a clue about how the gene works.
Studying the role of the protein produced by UBQNL2, they realized that the factor is crucial for disease processes far beyond ALS, and relevant for an array of brain conditions where protein aggregates occur — because it is part of the machinery clearing misfolded or aggregated proteins from the brain.
To do this, UBQNL2 first needs to untangle the protein clumps, which it does with the help of other factors. Then, it chops the proteins into pieces. Researchers discovered that the system is particularly important in the nucleus of cells, where other types of mechanisms for protein clearance are not active. If proteins start aggregating in the nucleus, UBQNL2 quickly enters it to clean out any obstructing protein waste.
“Our study has revealed a new mechanism by which nerve cells cope with protein clumps in general, which has implications for most neurodegenerative diseases and can open up avenues for new therapeutic interventions to treat these conditions in the future,” said Roland Hjerpe, PhD and first author of the study, in a news release.
The research team also discovered that when the gene is mutated in the way found in ALS patients, the factor cannot bind properly to one of the other factors needed for protein clearance, leading to an aggregation of proteins in mouse brains. Although ALS is a condition destroying the ability to move, mice with the mutation did not have movement problems — instead, they developed cognitive difficulties and neurodegeneration.
“The significance of this discovery goes beyond the role of UBQLN2 in motor-neuron disease with dementia,” Hjerpe said.
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