. Dysfunctional tubular endoplasmic reticulum constitutes a pathological feature of Alzheimer's disease. Mol Psychiatry. 2015 Dec 1; PubMed.


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  1. More than 10 years ago, Riqiang Yan’s lab identified the reticulon family members as major modulators of BACE1 β-secretase activity, and thus as important regulators of amyloid-β (Aβ) precursor protein (APP) cleavage, and generation of the Aβ peptide (He et al., 2004). The reticulons are structural proteins of the tubular endoplasmic reticulum (ER), and localize primarily to the tubular ER (Voeltz et al., 2006). Neurons of the CNS express primarily reticulon 3 (RTN3); interestingly, RTN3 is enriched in dystrophic neurites, particularly in Alzheimer’s disease (AD) brains. Moreover, it appears that RTN3 actively participates in the formation of the dystrophic neurites (Hu et al., 2006Shi et al., 2009). 

    While the tubular ER present in dendrites is relatively well studied, the penetration of ER tubules in axons is much less understood. Because the tubular ER was not considered a major site for axonal pathology in AD, the RTN3-containing compartments present in axons were not regarded—until recently—as part of the tubular ER, and it was assumed that, in axons, the reticulons had functions outside of the tubular ER. Over the past few years opinions have changed, and the new study from Riqiang Yan’s lab has now clearly established that a pathological feature of AD is the presence of a dysfunctional tubular ER in dystrophic axons, including at their terminals. These are findings that should not be overlooked by the AD research community, because they are extremely important. Moreover, the involvement of the reticulons—and thus of the tubular ER—in neuronal pathology, or in the neuronal response to the disease, is certainly not restricted to AD, and includes, for example, amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia, and multiple sclerosis (see, for a short review, Chiurchiu et al., 2014). 

    It is still unclear what the exact function of this specialized, axonal tubular ER compartment is; certainly it is not involved in protein synthesis. One possibility is that the axonal ER plays a role in calcium homeostasis. Another possibility is that the ER tubules are required for maintaining the structural and functional integrity of axonal mitochondria, as now proposed by Sharoar et al. The mitochondria-associated ER membranes (called MAM) have been, in fact, previously implicated in the pathogenic process in AD (Schon et al., 2013). We have recently reported that, in brainstem-derived neuronal cells, a tubular ER of defined biochemical composition is a vehicle for long-distance transport of disease-related cargo, such as APP N-terminal fragments (including the sAPPβ) (Muresan and Muresan, 2016). Moreover, proteins implicated in the pathogenic process in ALS, e.g., SOD1, FUS, and TDP-43, appear to be carried to the neurite terminals by associating with tubular projections of the ER, a transport mechanism that is insensitive to treatment with Brefeldin A (which blocks transport along the secretory route of conventional, trans-Golgi network-derived vesicles) (Muresan and Muresan, 2016). While there have been reports on the possibility of cargo delivery by ER-derived entities to remote destinations (mostly to dendrites) (Ehlers, 2013; Jeyifous et al., 2009; Valenzuela et al., 2011), the fact that a specialized ER compartment could have primarily a transport function is unexpected. Interestingly, we found that this unconventional form of long-distance transport performed by the tubular ER is regulated by neurofilaments (Muresan and Muresan, 2016; Muresan et al., 2014). The neurofilament network is disorganized in ALS (and probably in other neurodegenerative diseases too); therefore, one could ask whether this neurofilament abnormality could prevent the proper translocation of the tubular ER into the neuronal processes? Also, could the disruption of the axonal tubular ER be a more general pathogenic mechanism in neurodegenerative diseases? Time—and future studies—will tell.

    Zoia Ladescu Muresan contributed to this comment.


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