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Global Axonal Transport Rates are Unaltered in Htau Mice in vivo

Yuan, Aidong; Kumar, Asok; Sasaki, Takahiro; Duff, Karen; Nixon, Ralph A
Microtubule-based axonal transport is believed to become globally disrupted in Alzheimer's disease in part due to alterations of tau expression or phosphorylation. We previously showed that axonal transport rates along retinal ganglion axons are unaffected by deletion of normal mouse tau or by overexpression of wild-type human tau. Here, we report that htau mice expressing 3-fold higher levels of human tau in the absence of mouse tau also display normal fast and slow transport kinetics despite the presence of abnormally hyperphosphorylated tau in some neurons. In addition, markers of slow transport (neurofilament light subunit) and fast transport (snap25) exhibit normal distributions along optic axons of these mice. These studies demonstrate that human tau overexpression, even when associated with a limited degree of tau pathology, does not necessarily impair general axonal transport function in vivo.
PMCID:3819434
PMID: 23948900
ISSN: 1387-2877
CID: 542722

Neurofilaments at a glance

Yuan, Aidong; Rao, Mala V; Veeranna; Nixon, Ralph A
PMCID:3516374
PMID: 22956720
ISSN: 0021-9533
CID: 179149

Peripherin is a subunit of peripheral nerve neurofilaments: implications for differential vulnerability of CNS and peripheral nervous system axons

Yuan, Aidong; Sasaki, Takahiro; Kumar, Asok; Peterhoff, Corrinne M; Rao, Mala V; Liem, Ronald K; Julien, Jean-Pierre; Nixon, Ralph A
Peripherin, a neuronal intermediate filament protein implicated in neurodegenerative disease, coexists with the neurofilament triplet proteins [neurofilament light (NFL), medium (NFM), and heavy (NFH) chain] but has an unknown function. The earlier peak expression of peripherin than the triplet during brain development and its ability to form homopolymers, unlike the triplet, which are obligate heteropolymers, have supported a widely held view that peripherin and neurofilament triplets form separate filament systems. However, here, we demonstrate that, despite a postnatal decline in expression, peripherin is as abundant as the triplet in the adult PNS and exists in a relatively fixed stoichiometry with these subunits. Peripherin exhibits a distribution pattern identical to those of triplet proteins in sciatic axons and colocalizes with NFL on single neurofilaments by immunogold electron microscopy. Peripherin also coassembles into a single network of filaments containing NFL, NFM, and NFH with and without alpha-internexin in quadruple- or quintuple-transfected SW13vim(-) cells. Genetically deleting NFL in mice dramatically reduces peripherin content in sciatic axons. Moreover, peripherin mutations has been shown to disrupt the neurofilament network in transfected SW13vim(-) cells. These data show that peripherin and the neurofilament proteins are functionally interdependent. The results strongly support the view that, rather than forming an independent structure, peripherin is a subunit of neurofilaments in the adult PNS. Our findings provide a basis for its close relationship with neurofilaments in PNS diseases associated with neurofilament accumulation.
PMCID:3405552
PMID: 22723690
ISSN: 0270-6474
CID: 170430

The C-Terminal Domains of NF-H and NF-M Subunits Maintain Axonal Neurofilament Content by Blocking Turnover of the Stationary Neurofilament Network

Rao, Mala V; Yuan, Aidong; Campbell, Jabbar; Kumar, Asok; Nixon, Ralph A
Newly synthesized neurofilaments or protofilaments are incorporated into a highly stable stationary cytoskeleton network as they are transported along axons. Although the heavily phosphorylated carboxyl-terminal tail domains of the heavy and medium neurofilament (NF) subunits have been proposed to contribute to this process and particularly to stability of this structure, their function is still obscure. Here we show in NF-H/M tail deletion [NF-(H/M)(tailDelta)] mice that the deletion of both of these domains selectively lowers NF levels 3-6 fold along optic axons without altering either rates of subunit synthesis or the rate of slow axonal transport of NF. Pulse labeling studies carried out over 90 days revealed a significantly faster rate of disappearance of NF from the stationary NF network of optic axons in NF-(H/M)(tailDelta) mice. Faster NF disappearance was accompanied by elevated levels of NF-L proteolytic fragments in NF-(H/M)(tailDelta) axons. We conclude that NF-H and NF-M C-terminal domains do not normally regulate NF transport rates as previously proposed, but instead increase the proteolytic resistance of NF, thereby stabilizing the stationary neurofilament cytoskeleton along axons.
PMCID:3448626
PMID: 23028520
ISSN: 1932-6203
CID: 179098

The Myosin Va Head Domain Binds to the Neurofilament-L Rod and Modulates Endoplasmic Reticulum (ER) Content and Distribution within Axons

Rao, Mala V; Mohan, Panaiyur S; Kumar, Asok; Yuan, Aidong; Montagna, Lee; Campbell, Jabbar; Espreafico, Enilza M; Julien, Jean P; Nixon, Ralph A
The neurofilament light subunit (NF-L) binds to myosin Va (Myo Va) in neurons but the sites of interaction and functional significance are not clear. We show by deletion analysis that motor domain of Myo Va binds to the NF-L rod domain that forms the NF backbone. Loss of NF-L and Myo Va binding from axons significantly reduces the axonal content of ER, and redistributes ER to the periphery of axon. Our data are consistent with a novel function for NFs as a scaffold in axons for maintaining the content and proper distribution of vesicular organelles, mediated in part by Myo Va. Based on observations that the Myo Va motor domain binds to intermediate filament (IF) proteins of several classes, Myo Va interactions with IFs may serve similar roles in organizing organelle topography in different cell types
PMCID:3040190
PMID: 21359212
ISSN: 1932-6203
CID: 126479

The contributions of myelin and axonal caliber to transverse relaxation time in shiverer and neurofilament-deficient mouse models

Dyakin, Victor V; Chen, Yuanxin; Branch, Craig A; Yuan, Aidong; Rao, Mala; Kumar, Asok; Peterhoff, Corrinne M; Nixon, Ralph A
White matter disorders can involve injury to myelin or axons but the respective contribution of each to clinical course is difficult to evaluate non-invasively. Here, to develop a paradigm for further investigations of axonal pathology by MRI, we compared two genetic mouse models exhibiting relatively selective axonal or myelin deficits using quantitative MRI relaxography of the transverse relaxation times (T2) in vivo and ultrastructural morphometry. In HM-DKO mice, which lack genes encoding the heavy (NF-H) and medium (NF-M) subunits of neurofilaments, neurofilament content of large myelinated axons of the central nervous system (CNS) is markedly reduced in the absence of changes in myelin thickness and volume. In shiverer mutant mice, which lack functional myelin basic protein, CNS myelin sheath formation is markedly reduced but neurofilament content is normal. We observed increases in T2 in nearly all white matter in shiverer mice compared to their wild type, while more subtle increases in T2 were observed in HM-DKO in the corpus callosum. White matter T2 was generally greater in shiverer mice than HM-DKO mice. Ultrastructural morphometry of the corpus callosum, which exhibited the greatest T2 differences, confirmed that total cross-sectional area occupied by axons was similar in the two mouse models and that the major ultrastructural differences, determined by morphometry, were an absence of myelin and larger unmyelinated axons in shiverer mice and absence of neurofilaments in HM-DKO mice. Our findings indicate that T2 is strongly influenced by myelination state and axonal volume, while neurofilament structure within the intra-axonal compartment has a lesser effect upon single compartment T2 estimates
PMCID:2862816
PMID: 20226865
ISSN: 1095-9572
CID: 126489

Neurofilaments form a highly stable stationary cytoskeleton after reaching a critical level in axons

Yuan, Aidong; Sasaki, Takahiro; Rao, Mala V; Kumar, Asok; Kanumuri, Vivek; Dunlop, David S; Liem, Ronald K; Nixon, Ralph A
The ultrastructural view of the axonal cytoskeleton as an extensively cross-linked network of neurofilaments (NFs) and other cytoskeletal polymers contrasts with the dynamic view suggested by axonal transport studies on cytoskeletal elements. Here we reconcile these perspectives by showing that neurons form a large NF network along axons which is unequivocally stationary, metabolically stable, and maintained by NFs and nonfilamentous subunit assemblies undergoing slow transport by intermittent rapid movements and pauses. In mouse primary cortical neurons transfected with EGFP-NFL, formation of this stationary NF network requires a critical level of NFs, which explains its absence in NF-poor developing neurons studied previously. Most NFs at proximal axon regions were in a stationary structure coexisting with a smaller pool of moving EGFP-NFL assemblies that were mainly nonfilamentous. Distally along the same axon, EGFP-labeled NFL was much less abundant, and we detected only short filaments moving bidirectionally by slow transport (rapid movements and pauses) as previously described. In living mice, >25% of radiolabeled newly synthesized NFs remained in optic axons after slowly transported NFs had exited. Retained NF remained fixed over several months in a nonuniform distribution and exhibited exceptionally slow turnover (t(1/2) >2.5 months), implying that, at steady state, >90% of NFs in mature optic axons comprise the stationary cytoskeleton and <10% are undergoing slow transport. These findings reconcile in vitro and in vivo axonal transport observations, showing that slowly transported NFs or subunit oligomers are precursors to a highly stable stationary cytoskeletal network that supports mature axons
PMCID:2788791
PMID: 19741138
ISSN: 1529-2401
CID: 126492

Axonal transport rates in vivo are unaffected by tau deletion or overexpression in mice

Yuan, Aidong; Kumar, Asok; Peterhoff, Corrinne; Duff, Karen; Nixon, Ralph A
Elevated tau expression has been proposed as a possible basis for impaired axonal transport in Alzheimer's disease. To address this hypothesis, we analyzed the movement of pulse radiolabeled proteins in vivo along retinal ganglion cell (RGC) axons of mice that lack tau or overexpress human tau isoforms. Here, we show that the global axonal transport rates of slow and fast transport cargoes in axons are not significantly impaired when tau expression is eliminated or increased. In addition, markers of slow transport (neurofilament light subunit) and fast transport (snap25) do not accumulate in retinas and are distributed normally along optic axons in mice that lack or overexpress tau. Finally, ultrastructural analyses revealed no abnormal accumulations of vesicular organelles or neurofilaments in RGC perikarya or axons in mice overexpressing or lacking tau. These results suggest that tau is not essential for axonal transport and that transport rates in vivo are not significantly affected by substantial fluctuations in tau expression
PMCID:2814454
PMID: 18272688
ISSN: 1529-2401
CID: 94106

[Analysis of factors relating to clinical outcomes after total knee replacement] [Case Report]

Yuan, Aidong; Cai, Daozhang; Wang, Kun
OBJECTIVE: To analyze the outcomes and complications after total knee replacement (TKR) with posterior stabilized prosthesis (PS) and to investigate the influencing factors relating to outcomes. METHODS: From January 1998 to August 2004, 60 cases (74 knees) of osteoarthritis underwent TKR with PS. The outcomes were evaluated according to the HSS (hospital for special surgery) scoring. The difference in outcomes between patients with post-operative complications and without complications were compared. Pearson correlation was used to analyze postoperative outcomes and the pre-operative factors relating to patients. RESULTS: All 74 knees were followed up 42.5 months (24 to 94 months). The scores for HSS, pain, function, ROM muscle strength, flexion deformity and stability of knees after operation were 84.2 +/- 14.2, 25.7 +/- 6.9, 17.9 +/- 4.3, 13.1 +/- 2.0, 9.2 +/- 0.8, 8.1 +/- 0.4 and 9.3 +/- 0.1 respectively. They were improved to some extents, especially pain alleviation was remarkable. The excellent and good rate for outcome assessment was 90.5%. Among 74 knees, 10 cases suffered from post-operative complications, including 1 case of common peroneal nerve paralysis, two cases of wound faulty union, one case of wound infection, one case of joint infection, one case of stiff knee, two cases of deep vein thrombosis and 2 cases of patellofemoral joint complications. The excellent and good rate of outcome in patients with complications (60%) was much lower than that in patients without complication (95.3%),and there was significant difference between them (P < 0.05). Analysis for correlation showed that postoperative HSS score was positively correlative with the postoperative HSS score, pain and function score of knees. The correlation value was 0.523, 0.431 and 0.418 respectively (P < 0.01). Whereas, postoperative HSS score was not correlative with ROM, muscle strength, flexion deformity, stability of knee, age, weight and body mass index (P > 0.05). CONCLUSION: TKR with PS is an effective method for severe osteoarthritis. The outcomes after TKR have a positive correlation with the HSS score, pain and function score of knees before surgery. Complications associating with surgery have a negative influence on outcomes
PMID: 17419199
ISSN: 1002-1892
CID: 94107

Alpha-internexin is structurally and functionally associated with the neurofilament triplet proteins in the mature CNS

Yuan, Aidong; Rao, Mala V; Sasaki, Takahiro; Chen, Yuanxin; Kumar, Asok; Liem, Ronald K H; Eyer, Joel; Peterson, Alan C; Julien, Jean-Pierre; Nixon, Ralph A
Alpha-internexin, a neuronal intermediate filament protein implicated in neurodegenerative disease, coexists with the neurofilament (NF) triplet proteins (NF-L, NF-M, and NF-H) but has an unknown function. The earlier peak expression of alpha-internexin than the triplet during brain development and its ability to form homopolymers, unlike the triplet, which are obligate heteropolymers, have supported a widely held view that alpha-internexin and neurofilament triplet form separate filament systems. Here, we demonstrate, however, that despite a postnatal decline in expression, alpha-internexin is as abundant as the triplet in the adult CNS and exists in a relatively fixed stoichiometry with these subunits. Alpha-internexin exhibits transport and turnover rates identical to those of triplet proteins in optic axons and colocalizes with NF-M on single neurofilaments by immunogold electron microscopy. Alpha-internexin also coassembles with all three neurofilament proteins into a single network of filaments in quadruple-transfected SW13vim(-) cells. Genetically deleting NF-M alone or together with NF-H in mice dramatically reduces alpha-internexin transport and content in axons throughout the CNS. Moreover, deleting alpha-internexin potentiates the effects of NF-M deletion on NF-H and NF-L transport. Finally, overexpressing a NF-H-LacZ fusion protein in mice induces alpha-internexin and neurofilament triplet to aggregate in neuronal perikarya and greatly reduces their transport and content selectively in axons. Our data show that alpha-internexin and the neurofilament proteins are functionally interdependent. The results strongly support the view that alpha-internexin is a fourth subunit of neurofilaments in the adult CNS, providing a basis for its close relationship with neurofilaments in CNS diseases associated with neurofilament accumulation
PMID: 17005864
ISSN: 1529-2401
CID: 94108