N-acetyl-D-glucosamine kinase binds dynein light chain roadblock 1 and promotes protein aggregate clearance

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 alpha -synuclein (alpha -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.