Abstract
Accumulation of ubiquitinated protein aggregates is a common pathology associated with a number of neurodegenerative diseases and selective autophagy plays a critical role in their elimination. Although aging-related decreases in protein degradation properties may enhance protein aggregation, it remains unclear whether proteasome dysfunction is indispensable for ubiquitinated-protein aggregation in neurodegenerative diseases. Here, we show that N-oleoyl-dopamine and N-arachidonyl-dopamine, which are endogenous brain substances and belong to the N-acyldopamine (AcylDA) family, generate cellular inclusions through aggresome formation without proteasome inhibition. Although AcylDA itself does not inhibit proteasome activity in vitro, it activates the rearrangement of vimentin distribution to form a vimentin cage surrounding aggresomes and sequesters ubiquitinated proteins in aggresomes. The gene transcription of p62/SQSTM1 was significantly increased by AcylDAs, whereas the transcription of other ubiquitin-dependent autophagy receptors was unaffected. Genetic depletion of p62 resulted in the loss of ubiquitinated-protein sequestration in aggresomes, indicating that p62 is a critical component of aggresomes. Furthermore, AcylDAs accelerate the aggregation of mutant huntingtin exon 1 proteins. These results suggest that aggresome formation does not require proteasome dysfunction and AcylDA-induced aggresome formation may participate in forming cytoplasmic protein inclusions.
Highlights
Proteostasis alteration is a characteristic of aging brains and causes the deposition of protein inclusions related to various late-onset neurodegenerative diseases[1,2,3]
We suggest that cells can create protein aggregates or inclusions by sequestering ubiquitinated proteins in aggresomes without impairing protein degradation systems and that AcylDA-induced aggresome formation is involved in a pathway that controls protein inclusion formation in neurodegenerative diseases
To identify chemical compounds that induced p62 expression, we first generated a p62 expression reporter construct (p62PR-EGFP), in which the human p62 promoter[30] drove enhanced green fluorescent protein (EGFP) expression as shown in Fig. 1A, and the reporter construct was stably transfected into Neuro2a (N2a) cells
Summary
Proteostasis alteration is a characteristic of aging brains and causes the deposition of protein inclusions related to various late-onset neurodegenerative diseases[1,2,3]. As ubiquitinated-proteins including cytotoxic misfolded proteins are sequestered from the cytoplasmic pool by aggresome formation until the protein degradation systems are restored, it is thought that aggresome formation is a cytoprotective response against proteotoxicity by proteasome dysfunction or the accumulation of polyubiquitinated proteins[19,20,21,22,23]. We found that N-oleoyl-dopamine (OLDA) and N-arachidonyl-dopamine (NADA) induce p62/ SQSTM1 expression and aggresome formation without proteasome inhibition as their novel functions These compounds are endogenous lipid derivatives of dopamine belonging to the N-acyl-dopamine (AcylDA) family and have been detected in the rodent striatum[26,27]. We suggest that cells can create protein aggregates or inclusions by sequestering ubiquitinated proteins in aggresomes without impairing protein degradation systems and that AcylDA-induced aggresome formation is involved in a pathway that controls protein inclusion formation in neurodegenerative diseases
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