. Axonal neuregulin-1 regulates myelin sheath thickness. Science. 2004 Apr 30;304(5671):700-3. PubMed.


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  1. Comment by Gabriel Corfas, Kristine Roy, and Suzhen Chen
    Over the last decade, evidence implicating the growth factor neuregulin 1 (NRG1) and its receptors, the erbB tyrosine kinases, in myelination of the peripheral nervous system has been accumulating. The early studies examined the consequences of loss of NRG1-erbB function. For example, Garratt et al. (2000) showed that ablation of erbB2 in Schwann cells results in reductions of the number of Schwann cell precursors in the developing nerve and hypomyelination of sciatic nerve axons in the adult. Now, a paper by Nave's group (Michailov et al., 2004) has extended these findings by examining the outcome of both reductions and increases of NRG1-erbB signaling on myelin formation. As expected from the preceding evidence, this study found that reduction in NRG1 or erbB2 expression results in hypomyelination. The more surprising finding in this study is that overexpression of NRG1 in axons leads to increased myelin thickness in the sciatic nerve. These results indicate that NRG1 is part of the signaling mechanisms by which axons regulate the thickness of the myelin sheet produced by Schwann cells. Interestingly, this hypermyelination occurred only with overexpression of one NRG1 isoform, type III NRG1, which contains a cysteine-rich domain, but not with type I NRG1, which contains an Ig domain.

    It is important to note that the roles of NRG1-erbB signaling in peripheral nerves are not confined to myelin-producing Schwann cells. We recently reported (Chen et al., 2003) that NRG1-erbB signaling is critical for interactions between unmyelinated axons and non-myelinating Schwann cells. We found that blockade of erbB signaling in non-myelinating Schwann cells results in a progressive peripheral neuropathy with a late-onset degeneration of selected populations of primary sensory neurons. These results indicate that NRG1-erbB signaling in some peripheral glial cells is important for long-term survival of their associated neurons.

    We believe that the next important questions regarding the roles of NRG1-erbB signaling in neuron-glia interactions lie in the central nervous system, where the roles of these molecules are much less understood. The studies discussed above raise the question whether this signaling pathway is important for myelination in the brain. Moreover, the possibility that defects in NRG1-erbB signaling are implicated in neurodegenerative processes in the brain, similar to what we found in the periphery, needs to be examined.

    View all comments by Gabriel Corfas
  2. This paper describes an intriguing Drosophila model of tau phosphorylation causing tau neurotoxicity. So far, therapeutic approaches to tau pathology in AD did not progress beyond the preclinical stage and were mainly directed at the inhibition of the CDK5 and GSK3 kinases. However, the MARK pathway may offer more promising targets. We and others have recently shown that MARKs are activated by LKB1/Par-4 [1,2]. This may represent a neurotoxic signal which is not specific for AD pathology, since it was just shown that both LKB1 and MARK4 become rapidly upregulated in a murine stroke model [3].

    Since confirmation of the Drosophila model by mouse knockouts may be difficult due to the presence of four MARK genes—whereas flies possess only a single gene—we may need to await the development of specific MARK inhibitors, and see whether these are able to inhibit P-tau (and Aβ-?) induced neuronal cell death.

    View all comments by Gerard Drewes
  3. Being human and the myelin on small fibers: Implications for the dementias and multiple other neuropsychiatric disorders
    By examining mice, Michailov et al. (2004) might have given us an important lead about the mechanisms that make our brain (and the disorders that plague it) unique.

    The human brain is unique in its high myelin content and long developmental (myelination) phase that continues until approximately the age of 50 (Bartzokis et al., 2001). Although our extensive process of myelination underlies many of our brain’s unique capabilities, it likely also underlies its unique susceptibility to highly prevalent disorders of development (autism, ADHD, schizophrenia, drug use, depression), as well as degeneration (Alzheimer’s, Parkinson’s, Lewy body and other rarer diseases) (Bartzokis, 2004a, 2004b). The large axons on which primary processes (motor and sensory) depend myelinate fully and most extensively in infancy, and are largely spared in both developmental and degenerative brain diseases despite their size and high metabolic requirements. On the other hand, oligodendrocytes that differentiate later in development are increasingly complex cells that myelinate, increasing numbers of smaller caliber axons, making them more and more vulnerable. In this myelin model of human brain, these later differentiating cells represent the “Achilles’ heel” of our brain’s Internet (Bartzokis et al., 2001; Bartzokis et al., 2003).

    The paper by Michailov et al. (2004) adds an essential clue to the genetic underpinnings of the differentially susceptibility of small caliber axons to both hypo- as well as hypermyelination. Although they did not specifically focus on this observation, their data showed that changing in neuregulin-1 differentially impacted myelination of smaller diameter axons. Thus, the gross function of the mice (dependent primarily on large axons) remained essentially normal. However, in the framework of the myelin model of the human brain outlined above, the differential impact of neuregulin-1 on small diameter axons takes on disproportionate significance for human neuropsychiatric diseases.

    In the framework of the model, it is not surprising that defects in the region containing this gene are strongly associated with schizophrenia (Li et al., 2004; Steffanson et al., 2003), a disease whose onset is primarily in the teens and early twenties when smaller fibers are being myelinated. Patients with schizophrenia have been shown to have myelination deficits that become increasingly more pronounced as they approach middle age (Bartzokis et al., 2003; Bartzokis, 2002), and although they develop early dementia (hence, its original name of “dementia praecox”), their dementia is not of the Alzheimer’s type (reviewed in Bartzokis, 2004b). Again, in the framework of the model, the absence of severe Alzheimer’s disease lesions is not surprising since their development may require intact (“normal”) brain myelination. Thus, in older age, defects in the neuregulin genes that cause hypomyelination can be expected to be associated with non-Alzheimer’s dementias of earlier onset such as frontotemporal dementias or the risk of developing trauma-related disorders such as dementia pugilistica (reviewed in Bartzokis, 2004b), while defects in the genes that promote myelination may protect from degenerative disorders.

    Neuregulin-1 and other such molecular signals represent clear targets for investigating genetic variations that may have subtle but crucial contributions to the quadratic trajectory of human brain myelin content over the lifetime. In the framework of the model, medications that impact such normal molecular mechanisms that differentially impact myelination of smaller caliber fibers could be especially useful in a wide range of human brain disorders. Influencing different disease processes with the same pharmacologic intervention may be possible by targeting different time points of increased vulnerability in the lifelong trajectory of myelin development and its subsequent degeneration (reviewed in Bartzokis, 2004b).

    View all comments by George Bartzokis
  4. This excellent paper draws renewed attention to the (other) central problem in neurodegeneration in general and AD in particular: How does the tau pathology originate? This essentially boils down to the question of what is the initial kinase, i.e., the kinase that triggers the phosphorylation that eventually results in hyperphosphorylation of tau and instigates the deadly cascade ending in paired helical filaments, neurofibrillary tangles and cell death. In that respect, tau is definitely the prime suspect and candidate "executer" of neurons in many neurodegenerative disorders, including AD. The pathological definition of AD as "plaques + tangles" does not allow or permit the AD field to escape this problem, despite the fact that amyloid attracts 10 times (my wild guess) more attention than tau.

    Through the work of the Mandelkow lab and many others, the functions of MARK kinase have been defined in some detail, in terms of phosphorylating tau and other MAPs, and in terms of neurite outgrowth and polarization. What was missing was a definite link to pathology, and that is provided by this paper. The authors define PAR1 kinase as responsible for phosphorylation of serines 262 and 356 in tau, thereby causing cells to die. Many studies have indirectly implicated MARK, GSK-3, PKA, and CaMKII in phosphorylating these sites, but no animal study is yet available to validate these kinases as the physiological kinase for these sites.

    So, are "S262 and S356" going to be magical for tau pathology as "β and γ" are for amyloid pathology? At the least, these serine residues are located in the region of tau that matters most, i.e., the microtubule-binding domain, which, incidentally, is also the region that is littered with mutations giving rise to the family of tauopathies known as FTD, or frontotemporal dementia! Antibody 12E8 specifically detects pS262 and pS356 in the MTBD of tau (Seubert et al., 1995), and it is definitely going to be popular and in demand among tauists and perhaps baptists. As always, many questions and some caveats remain. For one, the authors use not wild-type human tau, but the FTD mutant tau-R406W. This might explain why the final outcome is cell death but no tau aggregates in whatever form. Moreover, the choice of this mutant might have been fortuitous, since it is the most C-terminal of all known clinical mutations, closely positioned to the AD2/PHF1 epitope that is important in binding to MT and in tau aggregation (Spittaels et al., 2000; Vandebroek et al., 2004). Further along the path to understand it all remains the question why no mice have yet been produced (or reported) with overexpression or deficiency of MARK? Those who have such mice available should come forward and inform the community what and how and where …

    View all comments by Fred Van Leuven