SUMO1 promotes Aβ production via the modulation of autophagy

Abstract

Autophagy is one of the main mechanisms in the pathophysiology of neurodegenerative disease. The accumulation of autophagic vacuoles (AVs) in affected neurons is responsible for amyloid-β (Aβ) production. Previously, we reported that SUMO1 (small ubiquitin-like modifier 1) increases Aβ levels. In this study, we explored the mechanisms underlying this. We investigated whether AV formation is necessary for Aβ production by SUMO1. Overexpression of SUMO1 increased autophagic activation, inducing the formation of LC3-II-positive AVs in neuroglioma H4 cells. Consistently, autophagic activation was decreased by the depletion of SUMO1 with small hairpin RNA (shRNA) in H4 cells. The SUMO1-mediated increase in Aβ was reduced by the autophagy inhibitors (3-methyladenine or wortmannin) or genetic inhibitors (siRNA targeting ATG5, ATG7, ATG12, or HIF1A), respectively. Accumulation of SUMO1, ATG12, and LC3 was seen in amyloid precursor protein transgenic mice. Our results suggest that SUMO1 accelerates the accumulation of AVs and promotes Aβ production, which is a key mechanism for understanding the AV-mediated pathophysiology of Alzheimer disease.

Ubiquitin-Dependent And Independent Signals In Selective Autophagy

“…Furthermore, other UBLs have been implicated in the regulation of aggrephagy. SUMO-1 has been suggested to regulate the formation of autophagic vesicles in neurons and thus influence the production of pathogenic amyloid-b [57]. FAT10 has been shown to bind to and regulate the solubility of polyQ proteins, and localize to aggresomes upon proteasome inhibition [58,59].…”

Ubiquitin signaling and autophagy

“…Autophagy receptors and Lys-63 poly-Ub chains are essential for aggrephagy, and their activity is maintained also by other Ub-related molecules. The ubiquitin-like proteins SUMO-1 and FAT10 bind and contribute to the formation of protein aggregates (59,60), whereas ISG15 binds to HDAC6 and p62 promoting lysosomal clearance of aggregates (61). Finally, BAG family members BAG1 and BAG3 compete for the HSP-bound polyubiquitinated substrates.…”

Cathepsin B-associated Activation of Amyloidogenic Pathway in Murine Mucopolysaccharidosis Type I Brain Cortex

“…The main pathological hallmark of AD is the deposition of senile plaques, mainly constituted by aggregates of β-amyloid peptides in the patient's brain thought to be the cause of massive neuroinflammation. Moreover, recent studies indicated that the formation of β-amyloid plaques and neurofibrillary tangles is also caused by defects in the autophagic-lysosomal pathway, essential for the removal of misfolded and aggregated proteins or damaged organelles [19][20][21][22][23]. In particular, accumulation of β-amyloid and phosphorylated Tau proteins have been reported in the mouse models of neurological MPS including MPS IIIB and MPS IIIC diseases [18,[24][25][26][27][28].…”