Sharoar MG, Shi Q, Ge Y, He W, Hu X, Perry G, Zhu X, Yan R.
Dysfunctional tubular endoplasmic reticulum constitutes a pathological feature of Alzheimer's disease.
Mol Psychiatry. 2015 Dec 1;
PubMed.
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., 2006; Shi 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.
References:
He W, Lu Y, Qahwash I, Hu XY, Chang A, Yan R.
Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation.
Nat Med. 2004 Sep;10(9):959-65. Epub 2004 Aug 1
PubMed.
Voeltz GK, Prinz WA, Shibata Y, Rist JM, Rapoport TA.
A class of membrane proteins shaping the tubular endoplasmic reticulum.
Cell. 2006 Feb 10;124(3):573-86.
PubMed.
Hu X, Shi Q, Zhou X, He W, Yi H, Yin X, Gearing M, Levey A, Yan R.
Transgenic mice overexpressing reticulon 3 develop neuritic abnormalities.
EMBO J. 2007 Jun 6;26(11):2755-67.
PubMed.
Shi Q, Hu X, Prior M, Yan R.
The occurrence of aging-dependent reticulon 3 immunoreactive dystrophic neurites decreases cognitive function.
J Neurosci. 2009 Apr 22;29(16):5108-15.
PubMed.
Chiurchiù V, Maccarrone M, Orlacchio A.
The role of reticulons in neurodegenerative diseases.
Neuromolecular Med. 2014 Mar;16(1):3-15. Epub 2013 Nov 12
PubMed.
Schon EA, Area-Gomez E.
Mitochondria-associated ER membranes in Alzheimer disease.
Mol Cell Neurosci. 2012 Aug 24;
PubMed.
Muresan V, Ladescu Muresan Z.
Shared Molecular Mechanisms in Alzheimer's Disease and Amyotrophic Lateral Sclerosis: Neurofilament-Dependent Transport of sAPP, FUS, TDP-43 and SOD1, with Endoplasmic Reticulum-Like Tubules.
Neurodegener Dis. 2016;16(1-2):55-61. Epub 2015 Nov 26
PubMed.
Ehlers MD.
Dendritic trafficking for neuronal growth and plasticity.
Biochem Soc Trans. 2013 Dec;41(6):1365-82.
PubMed.
Jeyifous O, Waites CL, Specht CG, Fujisawa S, Schubert M, Lin EI, Marshall J, Aoki C, de Silva T, Montgomery JM, Garner CC, Green WN.
SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway.
Nat Neurosci. 2009 Aug;12(8):1011-9. Epub 2009 Jul 20
PubMed.
Valenzuela JI, Jaureguiberry-Bravo M, Couve A.
Neuronal protein trafficking: emerging consequences of endoplasmic reticulum dynamics.
Mol Cell Neurosci. 2011 Dec;48(4):269-77. Epub 2011 Jul 19
PubMed.
Muresan V, Villegas C, Ladescu Muresan Z.
Functional interaction between amyloid-β precursor protein and peripherin neurofilaments: a shared pathway leading to Alzheimer's disease and amyotrophic lateral sclerosis?.
Neurodegener Dis. 2014;13(2-3):122-5. Epub 2013 Sep 4
PubMed.
Comments
Rutgers - New Jersey Medical School
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., 2006; Shi 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.
References:
He W, Lu Y, Qahwash I, Hu XY, Chang A, Yan R. Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation. Nat Med. 2004 Sep;10(9):959-65. Epub 2004 Aug 1 PubMed.
Voeltz GK, Prinz WA, Shibata Y, Rist JM, Rapoport TA. A class of membrane proteins shaping the tubular endoplasmic reticulum. Cell. 2006 Feb 10;124(3):573-86. PubMed.
Hu X, Shi Q, Zhou X, He W, Yi H, Yin X, Gearing M, Levey A, Yan R. Transgenic mice overexpressing reticulon 3 develop neuritic abnormalities. EMBO J. 2007 Jun 6;26(11):2755-67. PubMed.
Shi Q, Hu X, Prior M, Yan R. The occurrence of aging-dependent reticulon 3 immunoreactive dystrophic neurites decreases cognitive function. J Neurosci. 2009 Apr 22;29(16):5108-15. PubMed.
Chiurchiù V, Maccarrone M, Orlacchio A. The role of reticulons in neurodegenerative diseases. Neuromolecular Med. 2014 Mar;16(1):3-15. Epub 2013 Nov 12 PubMed.
Schon EA, Area-Gomez E. Mitochondria-associated ER membranes in Alzheimer disease. Mol Cell Neurosci. 2012 Aug 24; PubMed.
Muresan V, Ladescu Muresan Z. Shared Molecular Mechanisms in Alzheimer's Disease and Amyotrophic Lateral Sclerosis: Neurofilament-Dependent Transport of sAPP, FUS, TDP-43 and SOD1, with Endoplasmic Reticulum-Like Tubules. Neurodegener Dis. 2016;16(1-2):55-61. Epub 2015 Nov 26 PubMed.
Ehlers MD. Dendritic trafficking for neuronal growth and plasticity. Biochem Soc Trans. 2013 Dec;41(6):1365-82. PubMed.
Jeyifous O, Waites CL, Specht CG, Fujisawa S, Schubert M, Lin EI, Marshall J, Aoki C, de Silva T, Montgomery JM, Garner CC, Green WN. SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway. Nat Neurosci. 2009 Aug;12(8):1011-9. Epub 2009 Jul 20 PubMed.
Valenzuela JI, Jaureguiberry-Bravo M, Couve A. Neuronal protein trafficking: emerging consequences of endoplasmic reticulum dynamics. Mol Cell Neurosci. 2011 Dec;48(4):269-77. Epub 2011 Jul 19 PubMed.
Muresan V, Villegas C, Ladescu Muresan Z. Functional interaction between amyloid-β precursor protein and peripherin neurofilaments: a shared pathway leading to Alzheimer's disease and amyotrophic lateral sclerosis?. Neurodegener Dis. 2014;13(2-3):122-5. Epub 2013 Sep 4 PubMed.
Make a Comment
To make a comment you must login or register.