Gephyrin alterations due to protein accumulation stress are reduced by the lysosomal modulator Z-Phe-Ala-diazomethylketone.
Abstract
Inhibitory neurotransmission is important for brain function and requires specific transmitter receptors that are organized in synaptic domains. Gephyrin is a cytoskeletal organization protein that binds tubulin and plays an important role in clustering and organizing select inhibitory neurotransmitter receptors. Here, we tested if gephyrin is altered by protein accumulation stress that is common in age-related neurodegenerative disorders. For this, we used the hippocampal slice model that has been shown to exhibit chloroquine (CQN)-induced protein accumulation, microtubule destabilization, transport failure, and declines in excitatory neurotransmitter receptors and their responses. In addition to the decreases in excitatory receptor subunits and other glutamatergic markers, we found that gephyrin isoforms were reduced across the CQN treatment period. Associated with this decline in gephyrin levels was the production of three gephyrin breakdown products (GBDPs) of 30, 38, and 48 kDa. The induced effects on gephyrin were tested for evidence of recovery through enhancement of lysosomal function that is known to promote protein clearance and microtubule integrity. Using the lysosomal modulator Z-Phe-Ala-diazomethylketone (PADK), g...Continue Reading
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