Cell Death and Disease · 2020 · 20 citations · 33 references
Life SciencesMolecular BiologyNeuroscienceMolecular Cell BiologyMolecular NeuroscienceNeurodegenerationMolecular Basis Of NeurodegenerationNeurodegeneration MechanismsNeurodegenerative DiseasesNeurodegenerative DisordersProtein AggregationProtein Aggregation DisordersAggregate RemovalAggregationAlpha-synuclein AggregationDynein FunctionNeuronal Protein AggregationProtein Aggregate RemovalProtein AggregatesProtein Aggregation In Neurons
Abstract Emerging evidence indicates that neurodegenerative diseases (NDs) result from a failure to clear toxic protein aggregates rather than from their generation. We previously showed N -acetylglucosamine kinase (NAGK) promotes dynein functionality and suggested this might promote aggregate removal and effectively address proteinopathies. Here, we report NAGK interacts with dynein light chain roadblock type 1 (DYNLRB1) and efficiently suppresses mutant huntingtin (mHtt) (Q74) and α-synuclein (α-syn) A53T aggregation in mouse brain cells. A kinase-inactive NAGK D107A also efficiently cleared Q74 aggregates. Yeast two-hybrid selection and in silico protein–protein docking analysis showed the small domain of NAGK (NAGK-D S ) binds to the C-terminal of DYNLRB1. Furthermore, a small peptide derived from NAGK-D S interfered with Q74 clearance. We propose binding of NAGK-D S to DYNLRB1 ‘pushes up’ the tail of dynein light chain and confers momentum for inactive phi- to active open-dynein transition.
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