Reduced autophagy leads to reduction of GABA-A receptors
Mechanistically, excess p62 binds and sequesters GABAA receptoreassociated protein (GABARAP), an adapter that regulates endocytic GABAAR trafficking, leading to limited availability of GABARAP for surface presentation of GABAARs and selective downmodulation of GABA neurotransmission in Ulk2þ/ pyramidal neurons. (R1)
P62 here, is a protein that binds to other proteins that needs to be degraded during autophagy. When autophagy is not happening, there is accumulation of p62, which can bind to many proteins/enzymes, causing changes in cellular functions.
This paper describes that accumulated p62 binds to a protein that regulates transport of GABA-A receptors to the membrane. This leads to reduction of GABA-A receptors on the cellular surface.
I suspect this might be related to the root cause of TS, where GABAergic neurotransmission is not sufficient.