Noninflammatory cerebral vasculopathy associated with recurrent ischemic strokes.

Recurrent ischemic strokes often have uncommon causes in young adults. Vascular abnormalities may be considered as a possible etiology. We report a 36-year-old man who experienced recurrent cryptogenic ischemic strokes despite medical therapy.

PyK2 and FAK connections to p190Rho guanine nucleotide exchange factor regulate RhoA activity, focal adhesion formation, and cell motility.

Integrin binding to matrix proteins such as fibronectin (FN) leads to formation of focal adhesion (FA) cellular contact sites that regulate migration. RhoA GTPases facilitate FA formation, yet FA-associated RhoA-specific guanine nucleotide exchange factors (GEFs) remain unknown. Here, we show that proline-rich kinase-2 (Pyk2) levels increase upon loss of focal adhesion kinase (FAK) in mouse embryonic fibroblasts (MEFs).

Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot-Marie-Tooth disease-linked mutations in NFL and HSPB1.

Mutations in neurofilament light (NFL) subunit and small heat-shock protein B1 (HSPB1) cause autosomal-dominant axonal Charcot-Marie-Tooth disease type 2E (CMT2E) and type 2F (CMT2F). Previous studies have shown that CMT mutations in NFL and HSPB1 disrupt NF assembly and cause aggregation of NFL protein. In this study, we investigate the role of aggregation of NFL protein in the neurotoxicity of CMT mutant NFL and CMT mutant HSPB1 in motor neurons.

The complex relation between genotype and phenotype in motor neuron disease.

The success in mapping genetic loci and identifying mutant genes in familial neurodegenerative disease has outpaced our ability to understand the linkage between genotype and phenotype of disease. The results have led to a backlog of genetic information with limited clarification of underlying disease mechanisms. A major dilemma is how mutations in widely expressed proteins lead to degeneration or dysfunction of small subsets of neurons.

Role of neurofilament aggregation in motor neuron disease.

A major question in the pathogenesis of motor neuron disease is why motor neurons are selectively susceptible to mutations in widely expressed gene products. Reexamination of motor neuron degeneration due to alterations of neurofilament (NF) expression suggests that disruption of assembly with aggregation of the light neurofilament (NFL) protein may be an upstream event and contributing factor leading to the preferential degeneration of motor neurons. The implications of these findings are that aggregation of NFL is not only a triggering mechanism to account for the hallmark aggregates of NF protein in sporadic and familial forms of amyotrophic lateral sclerosis, but that aggregates of NFL may also promote aggregation of wildly expressed proteins that are destabilized by missense mutations, such as by mutations in superoxide dismutase-1 protein.