Abstract
Reticulon proteins (RTNs), consisting of RTN1 to RTN4, were previously shown to interact with BACE1 by negatively modulating its secretase activity. In RTN3-null mice, RTN1 expression was slightly elevated. To understand the in vivo role of RTN1, we generated RTN1-null mice and compared the effects of RTN1 and RTN3 on BACE1 modulation. We show that RTN1 is mostly expressed by neurons and not by glial cells under normal conditions, similar to the expression of RTN3. However, RTN1 is more localized in dendrites and is an excellent marker for dendrites of Purkinje cells, while RTN3 expression is less evident in dendrites. This differential localization also correlates with their associations with amyloid plaques in Alzheimer’s brains: RTN3, but not RTN1, is abundantly enriched in dystrophic neurites. RTN3 deficiency causes elevation of BACE1 protein levels, while RTN1 deficiency shows no obvious effects on BACE1 activity due to compensation by RTN3, as RTN1 deficiency causes elevation of RTN3 expression. Hence, expression of RTN1 and RTN3 is tightly regulated in mouse brains. Together, our data show that RTN1 and RTN3 have differential effects on the formation of senile plaques in Alzheimer’s brains and that RTN3 has a more prominent role in Alzheimer’s pathogenesis.
Highlights
The reticulons (RTNs) are a protein family with a characteristic C-terminal membrane-bound reticulon-homology domain (RHD)[1,2,3]
RTN1 was the first Reticulon proteins (RTNs) member cloned as a neuroendocrine-specific protein[22], initially characterized by Northern blot detection of RTN1 isoforms in neuroendocrine cell lines and a primary carcinoid lung tumor
Since both RTN1 and RTN3 are expected to shape tubular ER5, such a distinct distribution of RTN1 and RTN3 in dendrites suggests that each RTN member is likely to exert a unique biological function in cells or neurons in addition to certain shared biochemical functions
Summary
The reticulons (RTNs) are a protein family with a characteristic C-terminal membrane-bound reticulon-homology domain (RHD)[1,2,3]. The RHD domain in mouse and human is organized such that there are two transmembrane-anchoring stretches separated by a 66 amino acid-long loop and a short C-terminal tail. This domain is required for localizing RTN on the endoplasmic reticulum (ER) membrane and for shaping tubular ER structure[4, 5]. The effects of RTN3 deficiency on Aβ generation and amyloid deposition in mice is weak[12], likely due to compensation by other RTN members in neurons. RTN1 is richly expressed in neurons similar to RTN3, it exhibits much weaker effects on BACE1 expression and is more weakly associated with dystrophic neurites in Alzheimer’s amyloid plaques. With Alzheimer’s disease (AD) pathology than RTN1, and this difference is likely related to unique sequences that are present in RTN1 and RTN3 as well as their differential localizations in neruites
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