Glial cell line-derived neurotrophic factor (GDNF), a known survival factor for neurons, has recently been shown to stimulate the migration of Schwann cells (SCs) and to enhance myelination. GDNF exerts its biological effects by activating the Ret tyrosine kinase in the presence of glycosylphosphatidylinositol-linked receptor, GDNF family receptor (GFR) a1. In Ret-negative cells, the alternative transmembrane coreceptor is the 140-kDa isoform of neural cell adhesion molecule (NCAM) associated with a non-receptor tyrosine kinase Fyn. We confirmed that GDNF, GFRa1 and NCAM are expressed in neonatal rat SCs. We found that GDNF induces an increase in the partitioning of NCAM and heparan sulfate proteoglycan agrin into lipid rafts and that heparinase inhibits GDNFsignaling in SCs. In addition to activation of extracellular signal-regulated kinases, and phosphorylation of cAMP response element binding protein, we found that cAMPdependent protein kinase A and protein kinase C are involved in GDNF-mediated signaling in SCs. Although GDNF did not promote the differentiation of purified SCs into the myelinating phenotype, it enhanced myelination in neuron-SC cocultures. We conclude that GDNF utilizes NCAM signaling pathways to regulate SC function prior to myelination and at early stages of myelin formation.

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Hypertonia, which results from motor pathway defects in the central nervous system (CNS), is observed in numerous neurological conditions, including cerebral palsy, stroke, spinal cord injury, stiff-person syndrome, spastic paraplegia, dystonia and Parkinson disease. Mice with mutation in the hypertonic (hyrt) gene exhibit severe hypertonia as their primary symptom. Here we show that hyrt mutant mice have much lower levels of gamma-aminobutyric acid type A (GABA(A)) receptors in their CNS, particularly the lower motor neurons, than do wild-type mice, indicating that the hypertonicity of the mutants is likely to be caused by deficits in GABA-mediated motor neuron inhibition. We cloned the responsible gene, trafficking protein, kinesin binding 1 (Trak1), and showed that its protein product interacts with GABA(A) receptors. Our data implicate Trak1 as a crucial regulator of GABA(A) receptor homeostasis and underscore the importance of hyrt mice as a model for studying the molecular etiology of hypertonia associated with human neurological diseases.

Argyrophilic grain disease (AGD) is a progressive degenerative disease of the human brain, the prevalence of which increases with advancing age. The features of AGD in autopsied brains from 32 centenarians were studied using phosphorylated tau (AT8) immunostaining combined with Gallyas-Braak staining and 4R tau-specific antibody (RD4) immunostaining. Ten of 32 centenarians were diagnosed as AGD, yielding an overall frequency of 31.3%. In the demented group, nine (39.1%) of 23 cases were found with argyrophilic grains (AGs), while in the non-demented group, AGs were found in only one (11.1%) of nine cases, the difference between them being significant (P<0.05). Among the cases with Alzheimer's disease (AD), five (41.7%) of 12 were found with AGs. One (25%) of four cases with senile dementia with tangles (SDT) also suffered from AGD. Dementia caused by "pure" AGD accounted for 13% (3/23) among demented subjects. Our findings indicated that there is a high frequency of AGD in centenarians. In agreement with previous studies, we favor the view that age may be one of the risk factors for AGD.

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