BACE2 degradation is mediated by both the proteasome and lysosome pathways

Abstract

Background: Alzheimer's disease is the most common neurodegenerative disease in the elderly. Amyloid-β protein (Aβ) is the major component of neuritic plaques which are the hallmark of AD pathology. β-site APP cleaving enzyme 1 (BACE1) is the major β-secretase contributing to Aβ generation. β-site APP-cleaving enzyme 2 (BACE2), the homolog of BACE1, might play a complex role in the pathogenesis of Alzheimer's disease as it is not only a θsecretase but also a conditional β-secretase. Dysregulation of BACE2 is observed in Alzheimer's disease. However, the regulation of BACE2 is less studied compared with BACE1, including its degradation pathways. In this study, we investigated the turnover rates and degradation pathways of BACE2 in both neuronal cells and non-neuronal cells. Results: Both lysosomal inhibition and proteasomal inhibition cause a time-and dose-dependent increase of transiently overexpressed BACE2 in HEK293 cells. The half-life of transiently overexpressed BACE2 protein is approximately 6 h. Moreover, the half-life of endogenous BACE2 protein is approximately 4 h in both HEK293 cells and mouse primary cortical neurons. Furthermore, both lysosomal inhibition and proteasomal inhibition markedly increases endogenous BACE2 in HEK293 cells and mouse primary cortical neurons. Conclusions: This study demonstrates that BACE2 is degraded by both the proteasome and lysosome pathways in both neuronal and non-neuronal cells at endogenous level and in transient overexpression system. It indicates that BACE2 dysregulation might be mediated by the proteasomal and lysosomal impairment in Alzheimer's disease. This study advances our understanding of the regulation of BACE2 and provides a potential mechanism of its dysregulation in Alzheimer's disease.

A critical role for hepatic protein arginine methyltransferase 1 isoform 2 in glycemic control

“…Treatment with gluconeogenic stimulating hormone, glucagon, dramatically extended the half‐life of PRMT1 from 1.6 to 3 hours when primary hepatocytes from WT mice were treated with cycloheximide, a commonly used protein synthesis inhibitor 22 (Figure 1C). Further investigation revealed that increased PRMT1 protein accumulation was observed in the primary hepatocytes treated with a proteasome inhibitor MG132 22 but not NH 4 Cl, a lysosome inhibitor, 23 suggesting that proteasomal pathways may be involved (Figure S1A,B).…”

“…treated with cycloheximide, a commonly used protein synthesis inhibitor 22 ( Figure 1C). Further investigation revealed that increased PRMT1 protein accumulation was observed in the primary hepatocytes treated with a proteasome inhibitor MG132 22 but not NH 4 Cl, a lysosome inhibitor, 23 suggesting that proteasomal pathways may be involved ( Figure S1A,B). In addition to being stimulated by glucagon after prolonged fasting, gluconeogenesis is also governed by the suppressive effects of insulin postprandially.…”

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

“…Supporting the role of a concomitant impairment of autophagy and UPS in AD, recent studies show that BACE2, a β-site APP-cleaving enzyme which contributes to Aβ generation, is degraded by both the UPS and autophagy in neuronal and non-neuronal cells [171]. This suggests that BACE2 dysregulation and Aβ accumulation might be due to autophagy and UPS impairment in AD.…”

The Labyrinthine Landscape of APP Processing: State of the Art and Possible Novel Soluble APP-Related Molecular Players in Traumatic Brain Injury and Neurodegeneration

“…In this regard, both clusterin-JMR binding and JMR mutations prevent APP θ-cleavage, favouring β-cleavage of nascent APP and worsening AD symptoms [ 72 ]. Indeed, θ-secretase has been reported to be dysregulated in AD and this dysregulation has been hypothesised to be mediated by proteasomal and lysosomal impairments observed in AD [ 73 ]. However, since θ-secretase regulation has been less investigated compared to β-secretase 1, further studies are needed to elucidate its contribution to AD as well as putative drug target.…”