Novel roles of cytoplasmic ATM and ATR in neurodegenerative diseases

Abstract

ATM (ataxia-telangiectasia mutated) and ATR (ATM and Rad3-related) are two large protein kinases of the PIKK family. Their roles in DNA damage repair in the cell nucleus have been well studied. Increasingly, however, additional roles in the cell cytoplasm are becoming apparent, although full range of these functions remain to be clarified. Here I report that both ATM and ATR associate with synaptic vesicles. In the synapse as in the nucleus, the two proteins appear to play related, but non-overlapping roles. ATM associates with excitatory synaptic vesicles while ATR is located on inhibitory synaptic vesicles and Chromogranin A (CgA)-containing dense core vesicles. Their vesicle associations are not dependent on their kinase activity although their activities in the synaptic region are. Unexpectedly, both ATM and ATR interact with vesicle endocytosis related proteins, clathrin and AP2 complex subunits. Both in vivo and in vitro, when ATM levels drop, ATR expression is rapidly increased and vice versa. The reciprocity also establishes an excitation/inhibition (E/I) balance, important for neuronal circuits. Neurons lacking ATM display decreased excitatory and increased inhibitory signals. And the signaling goes both ways; pharmacologically altering either excitatory or inhibitory dominance, also changes both ATM and ATR expression levels. These results demonstrate that cytoplasmic components of ATM/ATR play important roles in synaptic vesicle regulation and their expression levels influence the E/I balance in neuronal circuitry. In exploring the regulation of ATM activity in cytoplasm, I have found that ATM degradation is through autophagy pathway while the degradation of ATR is dependent on ubiquitin proteasome systems (UPS). Furthermore, I provide evidence that ATM not only involved in synaptic vesicle trafficking, it is also involved in GLUT4 (glucose transporter type 4) trafficking and lysosome regulation. ATM deficient neurons show accumulated lysosomes in perinuclear regions, resulting in more retrograde, and less anterograde, transport of lysosomes. I show that this process is regulated by the physical interaction of ATM with DYNLL1. Finally, I show that ATM helps maintain lysosomal pH by way of the proton pump ATP6V1A. Activated ATM promotes GLUT4 translocation to plasma membrane, while blocking ATM kinase inhibits this movement resulting in GLUT4 trafficking to lysosomes and the downregulation of glucose uptake capacity. I propose that these findings offer a novel view of the full neurological and cognitive picture of A-T.

Date of Award	2018
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology