Neuronal aggregates: formation, clearance, and spreading

Abstract

Proteostasis is maintained by multiple cellular pathways, including protein synthesis, quality control, and degradation. An imbalance of neuronal proteostasis, associated with protein misfolding and aggregation, leads to proteinopathies or neurodegeneration. While genetic variations and protein modifications contribute to aggregate formation, components of the proteostasis network dictate the fate of protein aggregates. Here we provide an overview of proteostasis pathways and their interplay (particularly autophagy) with the metabolism of disease-related proteins. We review recent studies on neuronal activity-mediated regulation of proteostasis and transcellular propagation of protein aggregates in the nervous system. Targeting proteostasis pathways therapeutically remains an attractive but challenging task.

Figure 1. Proteostatic pathways regulate refolding, disaggregation, degradation and extracellular release of misfolded or disease related proteins

Cells and neurons respond to the presence of misfolded proteins by activating heat shock transcription factor (HSF1), which regulates the levels and functions of molecular chaperones (including Hsp70) and co-chaperone systems such as the heat shock response (HR). Hsp70 recognizes and binds misfolded proteins, assisting in refolding or disaggregating oligomers. Accumulation of misfolded protein aggregates in the lumen of the endoplasmic reticulum (ER) also induces ER stress, which subsequently engages the adaptive stress response known as the unfolded protein response (UPR). For example, one of the three components of UPR, inositol-requiring enzyme 1 (IRE1), catalyzes the synthesis of transcription factor X-box binding protein 1 (XBP1), which in turn controls a subset of UPR genes related to protein folding, translocation, and degradation. The two degradation systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal system, are responsible for the degradation of diverse protein substrates. Nascent polypeptides can be ubiquitinated and degraded by the proteasome via a process known as co-translational ubiquitination (CTU). Protein aggregates can be further deposited into aggresomes via dynein-dependent retrograde transport along the microtubule network. Autophagy is the primary pathway for the clearance of protein aggregates or aggresomes. Protein aggregates, which are recognized by autophagy receptors (AR), are sequestered within autophagosomes, which are then fused with endosomes to form amphisomes, and delivered to lysosomes for degradation. However, the intracellular protein aggregates (or fibrils) can also be secreted outside of the cells or neurons via exosomes that are derived from multi-vesicular bodies (MVB). In addition, an unconventional secretory pathway (CUPS) associated with autophagosomes (APG) or amphisomes may provide an alternative path for extracellular release of protein fibrils (exophagy).

Figure 2. Regulation of aggrephagy: selective autophagy degrades protein aggregates via autophagy receptors

Autophagy receptors, such as p62/SQSTM1, NBR1, OPTN1, ALFY and Tollip, mediate degradation of protein aggregates via selective autophagy by coupling autophagic cargos (ubiquitinated protein aggregates) and autophagy protein LC3. However, the binding affinity of certain autophagy receptors to either cargos (e.g. p62) or LC3 (e.g. OPTN1) is weak under normal condition. Phosphorylation of p62 by CK2, TBK1 and/or ULK1 enhances the affinity of p62 for ubiquitinated proteins (cargos), while phosphorylation of OPTN1 by TBK1 increases the binding of OPTN1 to autophagy modifier LC3. These modifications of p62 promote the selective degradation of protein aggregates by recruiting the autophagy machinery to the proximity of the aggregates.