NeuralCipher Research overview
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Autophagy has two distinct pathways, degradation and secretion. Autophagic degradation plays a pivotal role in proteostasis. However, the role of autophagic secretion in proteostasis maintenance is not fully understood. Here, we investigate how the blockade of autophagic secretion impairs proteostasis in SH-SY5Y cells. siRNA-mediated knockdown (KD) of a modulator for autophagosome formation, ATG5, BECN1, or FIP200 inhibited autophagic flux and secretion, causing accumulation of Triton X-100-insoluble α-synuclein (α-syn), which is an aggregate-prone protein responsible for neuronal loss in Parkinson's disease. The blockade of autophagic secretion by KD of t-SNARE SNAP23 or STX4 increased autophagic flux for p62 degradation, but these KDs induced enlargement and membrane damage of lysosomes as well as lysosomal dysfunction. SNAP23 or STX4 KD caused accumulation of Triton X-100-insoluble α-syn against induction of lysophagy. GBA KD showed lysosomal damage with the increase in autophagic secretion. RAB8A, a small GTPase regulator of polarized sorting to the plasma membrane, KD blocked autophagic secretion and produced lysosomal damage. SNAP23, STX4, or RAB8A KD further accelerated accumulation of Triton X-100-insoluble α-syn caused by a lysosomal protease inhibitor cocktail. Collectively, these findings suggest that SNAP23, STX4, or RAB8A KD blocks autophagic secretion and upregulates autophagic flux as a compensatory response to help maintain degradation. However, these KDs impair α-syn proteostasis because of lysosomal damage that they induce, counteracting compensatory effects of autophagic degradation, including lysophagy. Autophagic secretion and degradation may collaboratively form the clearance pathway required for maintaining lysosomal function by reducing the burden of aggregate-prone protein cargo.
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