. Reduced amyloid deposition in mice overexpressing RTN3 is adversely affected by preformed dystrophic neurites. J Neurosci. 2009 Jul 22;29(29):9163-73. PubMed.

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  1. First of all, I greatly appreciate Amber Dance for writing this news story. I would like to take this opportunity to add a few clarifications to this study. Finding abundant reticulon 3 (RTN3) aggregates accumulated in dystrophic neurites is indeed quite interesting. We have demonstrated that our RTN3 antibody (R458) marks abundant dystrophic neurites in surrounding amyloid plaques, and we named this population of dystrophic neurites as RTN3 immunoreactive dystrophic neurites (RIDNs). Angela Chang in Bruce Trapp’s lab (Cleveland Clinic) used the same antibody and replicated the same observation using postmortem brain samples from a different source (personal communication). We have noticed that detection of these abundant RIDNs may require an antibody that will recognize an epitope of aggregated RTN3 (discussed further below). Our antibody R459, which recognizes only the RTN3 monomer, detects only small numbers of dystrophic neurites in surrounding plaques. Stephen Strittmatter’s RTN4 (Nogo) antibody can also mark dystrophic neurites in human AD postmortem brain (Park et al., 2006).

    More interestingly, we found that transgenic mice overexpressing myc-tagged RTN3 driven by a murine prion promoter, a system developed by David Borchelt, develop abundant and dispersed RIDNs. Ultrastructural examination of RIDNs performed by Allan Levey’s group at Emory University revealed the presence of a large amount of protofibril-like aggregates near the axonal terminus as shown in our EMBO J article (Hu et al., 2007). Immuno-electron microscopy (EM) experiments, also performed at Emory University, suggest that the aggregates are enriched within membrane-enclosed structures whose sizes range from 3-5 μm, consistent with swollen neurites (Hu et al., 2007). A pre-embedding immuno-EM experiment performed by Xinghua Yin in the Trapp lab showed compacted and densely immunoreactive signals accumulated within a swelling axon (Hu et al., 2007).

    We initially had a concern as to whether RIDNs formation in RTN3 transgenic mice was due to an overexpression artifact or because of a tag problem. To address this, we have generated another line of transgenic mice that express wild-type human RTN3 under the control of an inducible promoter. Breeding this new line of mice with CaMK-tTA mice has now produced compound mice that will express the human RTN3 transgene. We have examined a couple of these new transgenic mice (eight months old) and found that RIDNs are also present in their hippocampus. Examination of elderly mouse brain has further confirmed that RIDNs are naturally occurring in their hippocampus (unpublished results). Hence, several lines of our studies all support that RTN3 is important in the formation of RIDNs.

    Biochemical studies showed that RTN3 tends to form dimers and high-molecular-weight RTN3 aggregates. A previous study also showed that RTN3 forms a dimer (Qi et al., 2003). Nogo (RTN4) has also been shown to form Nogo-dimers (Dodd et al., 2005). RTN proteins also form natural oligomers in the ER (Shibata et al., 2008). In addition, we found that transgenic mice expressing low levels of RTN3 transgene (line 1 and line 2) showed much less RIDN formation in their hippocampi (Hu et al., 2007). These results support that increased levels of RTN3 tend to form dimers, oligomers and aggregates, and should address Wataru Araki’s concerns. Our hypothesis that excessive aggregation of RTN3 promotes formation of RIDNs is supported by many data from biochemical, morphological, and animal model studies.

    References:

    . Nogo-A, -B, and -C are found on the cell surface and interact together in many different cell types. J Biol Chem. 2005 Apr 1;280(13):12494-502. PubMed.

    . Transgenic mice overexpressing reticulon 3 develop neuritic abnormalities. EMBO J. 2007 Jun 6;26(11):2755-67. PubMed.

    . Alzheimer precursor protein interaction with the Nogo-66 receptor reduces amyloid-beta plaque deposition. J Neurosci. 2006 Feb 1;26(5):1386-95. PubMed.

    . Pro-apoptotic ASY/Nogo-B protein associates with ASYIP. J Cell Physiol. 2003 Aug;196(2):312-8. PubMed.

    . The reticulon and DP1/Yop1p proteins form immobile oligomers in the tubular endoplasmic reticulum. J Biol Chem. 2008 Jul 4;283(27):18892-904. PubMed.

    View all comments by Riqiang Yan