Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals.

Toll is a cell surface receptor with well described roles in the developmental patterning of invertebrates and innate immunity in adult Drosophila. Mammalian toll-like receptors represent a family of Toll orthologs that function in innate immunity by recognizing molecular motifs unique to pathogens or injured tissue. One member in this family of pattern recognition receptors, toll-like receptor 3 (TLR3), recognizes viral double-stranded RNA and host mRNA. We examined the expression and function of TLRs in the nervous system and found that TLR3 is expressed in the mouse central and peripheral nervous systems and is concentrated in the growth cones of neurons. Activation of TLR3 by the synthetic ligand polyinosine:polycytidylic acid (poly I:C) or by mRNA rapidly causes growth cone collapse and irreversibly inhibits neurite extension independent of nuclear factor kappaB. Mice lacking functional TLR3 were resistant to the neurodegenerative effects of poly I:C. Neonatal mice injected with poly I:C were found to have fewer axons exiting dorsal root ganglia and displayed related sensorimotor deficits. No effect of poly I:C was observed in mice lacking functional TLR3. Together, these findings provide evidence that an innate immune pattern recognition receptor functions autonomously in neurons to regulate axonal growth and advances a novel hypothesis that this class of receptors may contribute to injury and limited CNS regeneration.

Medications and laboratory parameters as prognostic factors in amyotrophic lateral sclerosis.

We sought to examine the influence of medication usage and laboratory measurements on disease progression in amyotrophic lateral sclerosis (ALS). A database of 596 volunteers with ALS was generated from three clinical trials and one observational study. Disease course was measured by survival and three functional measures: the ALS Functional Rating Scale (ALSFRS), Vital Capacity (VC) and Maximum Voluntary Isometric Contraction (MVIC). Survival modeling was performed using Cox proportional hazards regression. The association of medication or laboratory measurements with disease progression was determined using a random effects model. In the multivariate analysis, survival was shorter in participants who took aspirin (HR =1.93, p =0.046); NSAIDs (HR =1.51, p =0.054); had low blood chloride (HR =0.76, p =0.020) or high bicarbonate levels (HR =1.37, p =0.006). Individuals who took calcium had better survival (HR =0.37, p =0.008) and a slower rate of decline of MVIC arm megascore (p =0.033). Vital capacity declined faster in individuals with lower serum chloride (p<0.0001), or higher bicarbonate (p =0.002) levels and those taking paracetamol (acetaminophen) (p =0.035). We conclude that aspirin or NSAID use may shorten survival in ALS, while calcium use may prolong survival. Our results support a need to further explore the role of neuroinflammation in the pathogenesis of ALS.

WAVE1 is required for oligodendrocyte morphogenesis and normal CNS myelination.

Myelin formation involves the outgrowth of an oligodendrocyte cell process that can be regarded as a giant lamellipodium because it is an actively growing structure with extruded cytoplasm. The actin cytoskeleton is critical to morphogenesis, but little is known about regulation of actin dynamics in oligodendrocytes. Wiskott-Aldrich syndrome protein family verprolin homologous (WAVE) proteins mediate lamellipodia formation; thus, we asked whether these proteins function in oligodendrocyte process formation and myelination. Here, we show that WAVE1 is expressed by oligodendrocytes and localizes to the lamella leading edge where actin polymerization is actively regulated. CNS WAVE1 expression increases at the onset of myelination. Expression of dominant-negative WAVE1 impaired process outgrowth and lamellipodia formation in cultured oligodendrocytes. Similarly, oligodendrocytes isolated from mice lacking WAVE1 had fewer processes compared with controls, whereas neurons and astrocytes exhibited normal morphology. In white matter of WAVE1-/- mice, we found regional hypomyelination in the corpus callosum and to a lesser extent in the optic nerve. In optic nerve from WAVE1-/- mice, there were fewer nodes of Ranvier but nodal morphology was normal, implicating a defect in myelin formation. Our in vitro findings support a developmentally dynamic and cell-autonomous role for WAVE1 in regulating process formation in oligodendrocytes. Additionally, WAVE1 function during CNS myelination appears to be linked to regional cues. Although its loss can be compensated for in many CNS regions, WAVE1 is clearly required for normal amounts of myelin to form in corpus callosum and optic nerve. Together, these data demonstrate a role for WAVE1 in oligodendrocyte morphogenesis and myelination.

Translating preclinical insights into effective human trials in ALS.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, adult-onset neurodegenerative disease characterized by selective dysfunction and death of motor neurons in the brain and spinal cord. The disease is typically fatal within 3-5 years of symptom onset. There is no known cure and only riluzole, which was approved by the FDA in 1996 for treatment of ALS, has shown some efficacy in humans. Preclinical insights from model systems continue to furnish ample therapeutic targets, however, translation into effective therapies for humans remains challenging. We present an overview of clinical trial methodology for ALS, including a summary rationale for target selection and challenges to ALS clinical research.