Remyelination protects neurons from DLK-mediated neurodegeneration.

Chronic demyelination is theorized to contribute to neurodegeneration and drive progressive disability in demyelinating diseases like multiple sclerosis. Here, we describe two genetic mouse models of inducible demyelination, one distinguished by effective remyelination, and the other by remyelination failure and persistent demyelination. By comparing these two models, we find that remyelination protects neurons from apoptosis, improves conduction, and promotes functional recovery. Chronic demyelination of neurons leads to activation of the mitogen-associated protein kinase (MAPK) stress pathway downstream of dual leucine zipper kinase (DLK), which ultimately induces the phosphorylation of c-Jun in the nucleus. Both pharmacological inhibition and CRISPR/Cas9-mediated disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. These findings provide direct experimental evidence that remyelination is neuroprotective and identify DLK inhibition as a potential therapeutic strategy to protect chronically demyelinated neurons.

Glial TGFß activity promotes neuron survival in peripheral nerves.

Maintaining long, energetically demanding axons throughout the life of an animal is a major challenge for the nervous system. Specialized glia ensheathe axons and support their function and integrity throughout life, but glial support mechanisms remain poorly defined. Here, we identified a collection of secreted and transmembrane molecules required in glia for long-term axon survival in vivo. We showed that the majority of components of the TGFß superfamily are required in glia for sensory neuron maintenance but not glial ensheathment of axons. In the absence of glial TGFß signaling, neurons undergo age-dependent degeneration that can be rescued either by genetic blockade of Wallerian degeneration or caspase-dependent death. Blockade of glial TGFß signaling results in increased ATP in glia that can be mimicked by enhancing glial mitochondrial biogenesis or suppressing glial monocarboxylate transporter function. We propose that glial TGFß signaling supports axon survival and suppresses neurodegeneration through promoting glial metabolic support of neurons.

Discoidin domain receptor regulates ensheathment, survival and caliber of peripheral axons.

Most invertebrate axons and small-caliber axons in mammalian peripheral nerves are unmyelinated but still ensheathed by glia. Here, we use Drosophila wrapping glia to study the development and function of non-myelinating axon ensheathment, which is poorly understood. Selective ablation of these glia from peripheral nerves severely impaired larval locomotor behavior. In an in vivo RNA interference screen to identify glial genes required for axon ensheathment, we identified the conserved receptor tyrosine kinase Discoidin domain receptor (Ddr). In larval peripheral nerves, loss of Ddr resulted in severely reduced ensheathment of axons and reduced axon caliber, and we found a strong dominant genetic interaction between Ddr and the type XV/XVIII collagen Multiplexin (Mp), suggesting that Ddr functions as a collagen receptor to drive axon wrapping. In adult nerves, loss of Ddr decreased long-term survival of sensory neurons and significantly reduced axon caliber without overtly affecting ensheathment. Our data establish essential roles for non-myelinating glia in nerve development, maintenance and function, and identify Ddr as a key regulator of axon-glia interactions during ensheathment and establishment of axon caliber.

Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination.

The form of Charcot-Marie-Tooth type 4B (CMT4B) disease caused by mutations in myotubularin-related 5 (MTMR5; also called SET binding factor 1, SBF1) shows a spectrum of axonal and demyelinating nerve phenotypes. This contrasts with the CMT4B subtypes caused by MTMR2 or MTMR13 (SBF2) mutations, which are characterized by myelin outfoldings and classic demyelination. Thus, it is unclear whether MTMR5 plays an analogous or distinct role from that of its homolog, MTMR13, in the peripheral nervous system (PNS). MTMR5 and MTMR13 are pseudophosphatases predicted to regulate endosomal trafficking by activating Rab GTPases and binding to the phosphoinositide 3-phosphatase MTMR2. In the mouse PNS, Mtmr2 was required to maintain wild-type levels of Mtmr5 and Mtmr13, suggesting that these factors function in discrete protein complexes. Genetic elimination of both Mtmr5 and Mtmr13 in mice led to perinatal lethality, indicating that the two proteins have partially redundant functions during embryogenesis. Loss of Mtmr5 in mice did not cause CMT4B-like myelin outfoldings. However, adult Mtmr5-/- mouse nerves contained fewer myelinated axons than control nerves, likely as a result of axon radial sorting defects. Consistently, Mtmr5 levels were highest during axon radial sorting and fell sharply after postnatal day seven. Our findings suggest that Mtmr5 and Mtmr13 ensure proper axon radial sorting and Schwann cell myelination, respectively, perhaps through their direct interactions with Mtmr2. This study enhances our understanding of the non-redundant roles of the endosomal regulators MTMR5 and MTMR13 during normal peripheral nerve development and disease.

Resuscitation status in psychogeriatric and general medical inpatients aged 65 years and older: a retrospective comparison study.

Objective The aims of the present study were to establish rates of resuscitation order documentation of patients aged ≥65 years from both psychogeriatric and general medical units and to compare patients on predictors of resuscitation status, particularly examining the effect of depression. Methods A retrospective case note audit of psychogeriatric (n=162) and general medical (n=135) unit admissions within a tertiary teaching hospital was performed. Multivariate logistic regression was used to determine significant clinical and demographic predictors of resuscitation status. Results Resuscitation orders were documented in more psychogeriatric (94.4%) than general medical (48.1%) files. Depression did not significantly predict resuscitation status in either group. Having undergone competency assessment significantly predicted resuscitation status for the total sample and separately for psychogeriatric and medical patients. Older age (overall sample), poorer prognosis (overall sample), living in residential care (overall sample and medical group) and self-consenting to resuscitation status (overall sample and medical group) significantly predicted resuscitation status. Conclusions Resuscitation orders were more frequently documented on the psychogeriatric unit. Further prospective analysis is needed of how resuscitation orders are made before depression is discounted as a predictor of end-of-life decision-making. What is known about the topic? Despite increased community, media and research attention to end-of-life decision-making, resuscitation preferences of older patients are often poorly documented. Existing research into patient clinical and demographic factors that influence end-of-life decision-making have largely focused on general medical rather than psychogeriatric settings. There is a need to investigate rates of resuscitation documentation in psychogeriatric and general medical units and specific factors associated with having a 'do not attempt resuscitation' order in place, particularly the effect of current depression on decision-making. What does this paper add? Resuscitation orders were more frequently documented on the psychogeriatric than medical unit. Depression was not a significant predictor of resuscitation status in either group of patients. Although having undergone a competency assessment, older age and poorer prognosis predicted not being for resuscitation for the total sample, living in residential care and self-consenting to resuscitation status predicted not being for resuscitation for the overall sample and the medical group specifically. What are the implications for practitioners? This paper suggests that the need for clinicians to ensure documentation of preferences is a focus of day-to-day work with older patients. Clinicians should consider patient competency in end-of-life decision-making and how factors associated with depression, such as helplessness, may be more closely related to resuscitation decision-making in older patients.

Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin.

Nephronophthisis (NPHP) is the most frequent genetic cause of chronic renal failure in children. Identification of four genes mutated in NPHP subtypes 1-4 (refs. 4-9) has linked the pathogenesis of NPHP to ciliary functions. Ten percent of affected individuals have retinitis pigmentosa, constituting the renal-retinal Senior-Loken syndrome (SLSN). Here we identify, by positional cloning, mutations in an evolutionarily conserved gene, IQCB1 (also called NPHP5), as the most frequent cause of SLSN. IQCB1 encodes an IQ-domain protein, nephrocystin-5. All individuals with IQCB1 mutations have retinitis pigmentosa. Hence, we examined the interaction of nephrocystin-5 with RPGR (retinitis pigmentosa GTPase regulator), which is expressed in photoreceptor cilia and associated with 10-20% of retinitis pigmentosa. We show that nephrocystin-5, RPGR and calmodulin can be coimmunoprecipitated from retinal extracts, and that these proteins localize to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells. Our studies emphasize the central role of ciliary dysfunction in the pathogenesis of SLSN.

Association of interferon-alpha-induced depression and improved treatment response in patients with hepatitis C.

Thirty-nine patients with hepatitis C viral infection on interferon-alpha (IFN-alpha) therapy were monitored weekly using the Beck Depression Inventory (BDI). Thirteen of thirty-nine patients (33%) developed IFN-alpha-induced major depressive disorder (MDD). During the course of IFN-alpha therapy, patients who became depressed were treated with citalopram, a selective serotonin reuptake inhibitor (SSRI) antidepressant. Results indicated that: (1) IFN-alpha response rates were significantly higher in those patients who developed IFN-alpha-induced MDD than in those who did not (end-of-treatment response (ETR) rates: 61.5% versus 26.9% and sustained viral response (SVR) rates: 38.5% versus 11.5%), (2) male patients with ETR to IFN-alpha therapy were, on average, approximately 33 pounds lighter in body weight than male patients who did not respond, and (3) gender, race, past history of MDD, and past history of substance abuse were not significantly associated with ETR. In conclusion, our findings suggest that IFN-alpha-induced MDD may be a predictor of a positive response to IFN-alpha therapy, or an indication of optimal dosing.