Regulation of peripheral nerve regeneration by the mTOR pathway

While neurons in the central nervous system: CNS) have limited capacity for regrowth after damage, neurons in the peripheral nervous system: PNS) have a robust ability to regenerate their axons following injury. Successful regeneration depends upon both extrinsic cues in the environment and the activation of intrinsic mechanisms to promote regrowth. A number of inhibitory molecules in the CNS environment that prevent axonal regrowth have been identified, but less is known regarding the signaling mechanisms that regulate regenerative ability in PNS neurons. Here, we explored multiple components of injury signaling in the PNS, including the retrograde transport of local axonal injury signals, enhancement of axonal growth capacity in the cell body, and the response of Schwann cells that myelinate the damaged axon. We first addressed how axonal injury triggers enhancement of axonal growth capacity in PNS neurons. The lack of regenerative ability of CNS neurons has been linked to downregulation of the mammalian target of rapamycin: mTOR) pathway. We find that PNS dorsal root ganglia neurons: DRGs) activate mTOR following damage, and that this activity contributes to enhance axonal growth capacity following injury. Furthermore, upregulation of mTOR activity by deletion of tuberous sclerosis complex 2: TSC2) in DRGs is sufficient to enhance axonal growth capacity in vitro and in vivo. We identified GAP-43 as a downstream target of this pathway, which may contribute to enhance regenerative ability. However, while genetic upregulation of mTOR activity in sensory neurons facilitates axonal regrowth, it also leads to a number of developmental and functional defects, including aberrant target innervation. Thus, while manipulation of the mTOR activity could stimulate nerve regeneration in the PNS, fine control of mTOR activity may be required for proper target innervation and functional recovery. mTOR activation in the damaged neuron is likely to represent one of several signaling events that mediate nerve regeneration. We thus also explored other aspects of peripheral nerve injury signaling, including the retrograde transport of local injury signals by axonal vesicles, and the response of myelinating Schwann cells to axonal damage. Our results indicate that several classes of signaling pathways occurring both in axons and Schwann cells cooperate to generate a robust regenerative response. A better understanding of the signaling pathways leading to increased regenerative growth ability of PNS neurons may guide new strategies to enhance nerve regeneration in the CNS

Ligand-Gated Chloride Channels Are Receptors for Biogenic Amines in C. elegans

Biogenic amines such as serotonin and dopamine are intercellular signaling molecules that function widely as neurotransmitters and neuromodulators. We have identified in the nematode Caenorhabditis elegans three ligand-gated chloride channels that are receptors for biogenic amines: LGC-53 is a high-affinity dopamine receptor, LGC-55 is a high-affinity tyramine receptor, and LGC-40 is a low-affinity serotonin receptor that is also gated by choline and acetylcholine. lgc-55 mutants are defective in a behavior that requires endogenous tyramine, which indicates that this ionotropic tyramine receptor functions in tyramine signaling in vivo. Our studies suggest that direct activation of membrane chloride conductances is a general mechanism of action for biogenic amines in the modulation of C. elegans behavior.National Institutes of Health (U.S.) (Grant GM24663)Howard Hughes Medical InstituteLife Sciences Research FoundationMedical Foundation, Inc

A combinatorial regulatory signature controls terminal differentiation of the dopaminergic nervous system in C. elegans

15 páginas, 7 figuras, 3 tablas.Terminal differentiation programs in the nervous system are encoded by cis-regulatory elements that control the expression of terminal features of individual neuron types. We decoded the regulatory information that controls the expression of five enzymes and transporters that define the terminal identity of all eight dopaminergic neurons in the nervous system of the Caenorhabditis elegans hermaphrodite. We show that the tightly coordinated, robust expression of these dopaminergic enzymes and transporters ("dopamine pathway") is ensured through a combinatorial cis-regulatory signature that is shared by all dopamine pathway genes. This signature is composed of an Ets domain-binding site, recognized by the previously described AST-1 Ets domain factor, and two distinct types of homeodomain-binding sites that act in a partially redundant manner. Through genetic screens, we identified the sole C. elegans Distalless/Dlx ortholog, ceh-43, as a factor that acts through one of the homeodomain sites to control both induction and maintenance of terminal dopaminergic fate. The second type of homeodomain site is a Pbx-type site, which is recognized in a partially redundant and neuron subtype-specific manner by two Pbx factors, ceh-20 and ceh-40, revealing novel roles of Pbx factors in the context of terminal neuron differentiation. Taken together, we revealed a specific regulatory signature and cognate, terminal selector-type transcription factors that define the entire dopaminergic nervous system of an animal. Dopaminergic neurons in the mouse olfactory bulb express a similar combinatorial transcription factor collective of Ets/Dlx/Pbx factors, suggesting deep phylogenetic conservation of dopaminergic regulatory programs.This work was funded by EMBO post-doctoral fellowships and Marie Curie Funds (to M.D. and N.F.), the New York Stem Cell Foundation Fellowships and the Spanish Government (SAF2011-26273) (to N.F), the NIH (R01NS039996-05; R01NS050266-03 to O.H.; R01GM30997 to M.C.; R01GM054510 to R.S.M.; and F32GM099160 to N.A.), and the Stavanger University Hospital (to M.D.). N.F is a NARSAD Young Investigator. O.H. is an Investigator of the Howard Hughes Medical Institute.Peer reviewe

Multi‐modal combination therapy rescued a frequent ischemic stroke patient due to giant cell arteritis

Ischemic stroke (IS) due to giant cell arteritis (GCA) is rare, but highly mortal. Here, we report a 72-year-old man who showed frequent IS with GCA. Initial therapy with prednisolone increased the frequency of IS, which disappeared after continuous multi-modal combination therapy with corticosteroids, immunosuppressive agents, antiplatelets, and statin. The present case was discharged with independent walk, suggesting that a multi-modal combination therapy rescued the GCA patient from frequent IS

Safety and Clinical Effects of a Muse Cell-Based Product in Patients With Amyotrophic Lateral Sclerosis: Results of a Phase 2 Clinical Trial

Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of motor neurons. Multilineage-differentiating stress-enduring (Muse) cells are unique endogenous stem cells that show therapeutic effects on motor function in ALS mouse models. We conducted a single-center open phase II clinical trial to evaluate the safety and clinical effects of repeated intravenous injections of an allogenic Muse cell-based product, CL2020, in patients with ALS. Five patients with ALS received CL2020 intravenously once a month for a total of six doses. The primary endpoints were safety and tolerability, and the secondary endpoint was the rate of change in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score. In addition, serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), sphingosine-1-phosphate (S1P), cerebrospinal fluid chitotriosidase-1 (CHIT-1), and neurofilament light chain (NfL) levels were evaluated. The CL2020 treatment was highly tolerated without serious side effects. The ALSFRS-R score change trended upward at 12 months post-CL2020 treatment compared with that at 3 months pre-administration, but the difference was not statistically significant. Among five patients diagnosed with ALS, three exhibited a decrease in the rate of ALSFRS-R score change, one demonstrated an increase, and another showed no change. In addition, the patients’ serum IL-6 and TNF-α levels and cerebrospinal fluid CHIT-1 and NfL levels increased for up to 6 months post-treatment; however, their serum S1P levels continuously decreased over 12 months. These findings indicate a favorable safety profile of CL2020 therapy. In the near future, a double-blind study of a larger number of ALS patients should be conducted to confirm the efficacy of ALS treatment with CL2020

Clinical and Pathological Benefits of Edaravone for Alzheimer's Disease with Chronic Cerebral Hypoperfusion in a Novel Mouse Model

Alzheimer's disease (AD) and chronic cerebral hypoperfusion (CCH) often coexist in dementia patients in aging societies. The hallmarks of AD including amyloid-β (Aβ)/phosphorylated tau (pTau) and pathology-related events such as neural oxidative stress and neuroinflammation play critical roles in pathogenesis of AD with CCH. A large number of lessons from failures of drugs targeting a single target or pathway on this so complicated disease indicate that disease-modifying therapies targeting multiple key pathways hold potent potential in therapy of the disease. In the present study, we used a novel mouse model of AD with CCH to investigate a potential therapeutic effect of a free radical scavenger, Edaravone (EDA) on AD with CCH via examining motor and cognitive capacity, AD hallmarks, neural oxidative stress, and neuroinflammation. Compared with AD with CCH mice at 12 months of age, EDA significantly improved motor and cognitive deficits, attenuated neuronal loss, reduced Aβ/pTau accumulation, and alleviated neural oxidative stress and neuroinflammation. These findings suggest that EDA possesses clinical and pathological benefits for AD with CCH in the present mouse model and has a potential as a therapeutic agent for AD with CCH via targeting multiple key pathways of the disease pathogenesis

Very rare solitary primary peripheral nerve onset cytotoxic molecule-positive peripheral T-cell lymphoma (PTCL)

Here we present the first report of solitary primary peripheral nerve onset cytotoxic molecule (CM)-positive peripheral T-cell lymphoma (PTCL) diagnosed after nerve biopsy. An 84-year-old female with rheumatoid arthritis (RA) complained of asymmetric severe tenderness in her upper limbs. The biopsy pathology revealed a direct invasion of CM-positive PTCL. When RA patients complain of numbness, tenderness, or weakness, lymphomatic peripheral nerve invasion should be considered

A Case of Malignant Peripheral Nerve Sheath Tumor with Rhabdomyoblastic Differentiation: Malignant Triton Tumor

Malignant peripheral nerve sheath tumors (MPNST) constitute a rare variety of soft tissue sarcomas thought to originate from Schwann cells or pluripotent cells of the neural crest. Malignant triton tumor (MTT), a very rare, highly aggressive soft tissue tumor, is a subgroup of MPNST and is comprised of malignant Schwann cells coexisting with malignant rhabdomyoblasts. We herein report the case of a 24-year-old man who presented a subcutaneous mass in his right thigh. The mass was removed surgically in its entirety and radiation therapy was applied locally to prevent tumor regrowth. Nonetheless, the patient died 10 months after surgery from metastases to the lung and brain. He presented neither cafe-au-lait spots nor cutaneous neurofibromas. The histopathology showed a transition from a neurofibroma to an MTT, making this the second report of an MTT arising from a neurofibroma without neurofibromatosis type 1, an autosomal dominant disorder with which 50-70% of tumors reported in previous studies were associated. A histopathological examination using immunostaining with desmin confirmed this diagnosis. MTT has a poorer prognosis than MPNST and should therefore be regarded as a distinct clinical entity

A Unique Case of Encephalopathy with an Elevated IgG-4 and Extremely High Interleukin-6 Level and Delayed Myelodysplastic Syndrome

We herein report a 75-year-old man who developed disturbed consciousness with polynuclear cell dominant pleocytosis and low glucose and extremely high interleukin (IL)-6 levels in his cerebrospinal fluid. The biopsy specimen from his right supraclavicular lymph node showed the infiltration of inflammatory cells positive for IgG, IgG4 and IL-6. Prednisolone and azathioprine administered under suspicion of IgG4-related disease (IgG4-RD) or multicentric Castleman's disease (MCD) successfully remitted the symptoms. However, he developed myelodysplastic syndrome (MDS) and died 18 months later. The extremely high IL-6 may have been related to the rare neurological manifestations and development of MDS in the present case

Case Study of an Intense Wind Event Associated with a Mesoscale Convective System in West Sumatera during the HARIMAU2006 Campaign

In this study, the processes responsible for an intense wind event that occurred in west Sumatera on November 19, 2006, during the first campaign of the Hydrometeorological ARay for Isv-Monsoon AUtomonitoring (HARIMAU) were investigated. Strong winds of 17 m s^[-1] and a sudden temperature drop of 5 K were observed at an X-band Doppler radar site associated with the passage of a convective system, and some houses were severely damaged. The convective system developed under an environment of strong low-level easterly vertical shear associated with the easterly region of an equatorial Rossby wave. The northern part of the convective system possessed qualitatively similar structures to midlatitude bow echoes, including the convex shape of the convective line, a descending rear-inflow jet positioned at its apex, and mesoscale vortices on both sides of the rear-inflow jet. The low-level wind behind the convective system formed a channel of strong easterly wind as it passed through an area of relatively low topography in the mountain range. The enhanced easterly wind was thought to contribute to the formation of the bow echo-like structure in the northern part of the convective system. This easterly rear-inflow jet was further accelerated in the convective system and descended near the leading edge, forming divergent strong winds at the surface. The sounding data that were taken after the passage of the convective system indicated that dry air appeared in the lower troposphere associated with an enhancement of the southerly component of the wind. An analysis of objective reanalysis data suggests that the southerly was probably associated with westward-propagating mixed Rossby-gravity waves with a period of approximately 5 days. It is suggested that the dry air intruded into the convective system across the back edge of the precipitation area and caused enhanced evaporative cooling, which resulted in the effective downward transport of the enhanced easterly momentum