Engagement of Neurotropic Viruses in Fast Axonal Transport: Mechanisms, Potential Role of Host Kinases and Implications for Neuronal Dysfunction

Much remains unknown about mechanisms sustaining the various stages in the life cycle of neurotropic viruses. An understanding of those mechanisms operating before their replication and propagation could advance the development of effective anti-viral strategies. Here, we review our current knowledge of strategies used by neurotropic viruses to undergo bidirectional movement along axons. We discuss how the invasion strategies used by specific viruses might influence their mode of interaction with selected components of the host’s fast axonal transport (FAT) machinery, including specialized membrane-bounded organelles and microtubule-based motor proteins. As part of this discussion, we provide a critical evaluation of various reported interactions among viral and motor proteins and highlight limitations of some in vitro approaches that led to their identification. Based on a large body of evidence documenting activation of host kinases by neurotropic viruses, and on recent work revealing regulation of FAT through phosphorylation-based mechanisms, we posit a potential role of host kinases on the engagement of viruses in retrograde FAT. Finally, we briefly describe recent evidence linking aberrant activation of kinase pathways to deficits in FAT and neuronal degeneration in the context of human neurodegenerative diseases. Based on these findings, we speculate that neurotoxicity elicited by viral infection may involve deregulation of host kinases involved in the regulation of FAT and other cellular processes sustaining neuronal function and survival

The ICF core sets for hearing loss project : international expert survey on functioning and disability of adults with hearing loss using the international classification of functioning, disability, and health (ICF)

OBJECTIVE : To identify relevant aspects of functioning, disability, and contextual factors for adults with hearing loss (HL) from hearing health professional perspective summarized using the ICF classification as reference tool. DESIGN : Internet-based cross-sectional survey using open-ended questions. Responses were analysed using a simplified content analysis approach to link concept to ICF categories according to linking rules. STUDY SAMPLE : Hearing health professionals (experts) recruited through e-mail distribution lists of professional organizations and personal networks of ICF core set for hearing loss steering committee members. Stratified sampling according to profession and world region enhanced the international and professional representation. RESULTS : Sixty-three experts constituted the stratified sample used in the analysis. A total of 1726 meaningful concepts were identified in this study, resulting in 209 distinctive ICF categories, with 106 mentioned by 5% or more of respondents. Most categories in the activities & participation component related to communication, while the most frequent environmental factors related to the physical environment such as hearing aids or noise. Mental functions, such as confidence or emotional functions were also frequently highlighted. CONCLUSIONS : More than half (53.3%) of the entire ICF classification categories were included in the expert survey results. This emphasizes the importance of a multidimensional tool, such as the ICF, for assessing persons with hearing loss.Oticon Foundation and Hörselforskningsfonden (Swedish hearing research foundation)http://informahealthcare.com/loi/ijahb201

The NF2 tumor suppressor regulates microtubule-based vesicle trafficking via a novel Rac, MLK and p38SAPK pathway

© Macmillan Publishers, 2013. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Oncogene 32 (2013): 1135–1143, doi:10.1038/onc.2012.135.Neurofibromatosis type 2 patients develop schwannomas, meningiomas and ependymomas resulting from mutations in the tumor suppressor gene, NF2, encoding a membrane-cytoskeleton adapter protein called merlin. Merlin regulates contact inhibition of growth and controls the availability of growth factor receptors at the cell surface. We tested if microtubule-based vesicular trafficking might be a mechanism by which merlin acts. We found that schwannoma cells, containing merlin mutations and constitutive activation of the Rho/Rac family of GTPases, had decreased intracellular vesicular trafficking relative to normal human Schwann cells. In Nf2−/− mouse Schwann (SC4) cells, re-expression of merlin as well as inhibition of Rac or its effector kinases, MLK and p38SAPK, each increased the velocity of Rab6 positive exocytic vesicles. Conversely, an activated Rac mutant decreased Rab6 vesicle velocity. Vesicle motility assays in isolated squid axoplasm further demonstrated that both mutant merlin and active Rac specifically reduce anterograde microtubule-based transport of vesicles dependent upon the activity of p38SAPK kinase. Taken together, our data suggest loss of merlin results in the Rac-dependent decrease of anterograde trafficking of exocytic vesicles, representing a possible mechanism controlling the concentration of growth factor receptors at the cell surface.This work was supported by NIH R01 CA118032 (to NR), and MBL research fellowships (to NR and GM), NIH R01 NS23868 (to STB)

The ICF core sets for hearing loss project : functioning and disability from the patient perspective

OBJECTIVE : To explore areas of functioning, disability, and environmental factors of adults with hearing loss (HL) by using the ICF classification as a tool to determine and document each element. DESIGN : A qualitative study applying mainly focus-group methodology was applied. STUDY SAMPLE : Thirty-six Dutch and South African adults (≥ 18 years of age) with HL (20-95 dB HL) who used oral communication as first communication. Summative content analysis was performed on the transcripts by linkage to appropriate ICF categories. RESULTS : 143 ICF categories were identified, most of which belonged to the Activities & Participation (d) component, closely followed by the Environmental factors component. Participants specifically mentioned categories related to oral communication and interaction. Assistive technology (such as hearing aids), noise, and support by and attitudes of others in the environment of the participants were considered highly influential for functioning and disability. CONCLUSIONS : The present study illustrates the complex and encompassing nature of aspects involved in functioning and disability of adults with HL. Findings highlight the necessity of using a multidimensional tool, such as the ICF, to map functioning and disability with hearing loss, allowing consideration and evaluation of aspects that are both internal and external.The Oticon Foundationhttp://www.tandfonline.com/loi/iija20hb2017Speech-Language Pathology and Audiolog

Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase

© The Author(s), 2013. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS ONE 8 (2013): e65235, doi:10.1371/journal.pone.0065235.Dying-back degeneration of motor neuron axons represents an established feature of familial amyotrophic lateral sclerosis (FALS) associated with superoxide dismutase 1 (SOD1) mutations, but axon-autonomous effects of pathogenic SOD1 remained undefined. Characteristics of motor neurons affected in FALS include abnormal kinase activation, aberrant neurofilament phosphorylation, and fast axonal transport (FAT) deficits, but functional relationships among these pathogenic events were unclear. Experiments in isolated squid axoplasm reveal that FALS-related SOD1 mutant polypeptides inhibit FAT through a mechanism involving a p38 mitogen activated protein kinase pathway. Mutant SOD1 activated neuronal p38 in mouse spinal cord, neuroblastoma cells and squid axoplasm. Active p38 MAP kinase phosphorylated kinesin-1, and this phosphorylation event inhibited kinesin-1. Finally, vesicle motility assays revealed previously unrecognized, isoform-specific effects of p38 on FAT. Axon-autonomous activation of the p38 pathway represents a novel gain of toxic function for FALS-linked SOD1 proteins consistent with the dying-back pattern of neurodegeneration characteristic of ALS.Support was provided by 2007/2008 Marine Biological Laboratory summer fellowships and NIH (NS066942A) grants to GM; Howard Hughes Medical Institute-USE Grant #52006287 to Hunter College of CUNY (LM); Muscular Dystrophy Association (MDA) and NIH (R01NS44170) grants to LJH; MDA and NIH (NS23868, NS23320, NS41170) grants to STB; NIH grant MH066179 to GB; NIH grants R01AG031311 and R01NS055951 to DMW; NIH (U01NS05225, R01NS050557, 1RC1NS068391, 1RC2NS070342) grants to RHB; R01NS067206 to DAB; ALS Association grants to GM, AT, RHB, and STB; and ALS/CVS Therapy Alliance grants to RHB, GM, AT, LJH, and DAB. RHB and AT received support from the Angel Fund. RHB also received support from the DeBourgknecht Fund for ALS Research, P2ALS and Project ALS

Mechanisms of Fast Axonal Transport Impairment by the HIV Glycoprotein gp120

Distal sensory polyneuropathy (DSP) is a prevalent neurological complication directly caused by human immunodeficiency virus (HIV). DSP is characterized by progressive dying-back degeneration of long sensory axons at the distal extremities, which originate from dorsal root ganglion (DRG) neurons. Gp120, a neurotoxic HIV glycoprotein that is overproduced and shed by infected macrophages, has been linked to DSP. However, the role that gp120 plays in promoting degeneration of DRG axons remains uncertain. For my dissertation, I hypothesized that gp120 exerts its neurotoxic effects inside DRG neurons. My research consisted of 2 specific aims. The first was to evaluate the mechanisms of internalization and intracellular location of gp120. Using immunocytochemical and pharmacological experiments, I defined the endosomal pathway for gp120 internalization. Additional experiments using compartmentalized microfluidic chambers revealed retrograde transport of gp120 from DRG axons to their cell bodies. Since dying-back neurodegeneration has been linked to impaired fast axonal transport (FAT), I hypothesized that intracellular gp120 inhibits FAT. My second aim was to identify intra-axonal signaling pathways underlying gp120-induced alterations in fast axonal transport. Gp120 was perfused in isolated squid axoplasm, revealing axon-specific effects of gp120 on fast axonal transport (FAT). Coperfusion of gp120 with inhibitors of certain regulatory kinases and phosphatases for FAT delineated the signaling pathways that gp120 activated to impair anterograde and retrograde FAT. These results were confirmed with biochemical assays and microtubule binding assays in a mammalian cell line. The unique reliance of neurons on FAT mechanisms suggests that gp120-induced activation of phosphotransferases in the axonal compartment might represent a critical pathogenic event in DSP