Botulinum Neurotoxin D Uses Synaptic Vesicle Protein SV2 and Gangliosides as Receptors

Botulinum neurotoxins (BoNTs) include seven bacterial toxins (BoNT/A-G) that target presynaptic terminals and act as proteases cleaving proteins required for synaptic vesicle exocytosis. Here we identified synaptic vesicle protein SV2 as the protein receptor for BoNT/D. BoNT/D enters cultured hippocampal neurons via synaptic vesicle recycling and can bind SV2 in brain detergent extracts. BoNT/D failed to bind and enter neurons lacking SV2, which can be rescued by expressing one of the three SV2 isoforms (SV2A/B/C). Localization of SV2 on plasma membranes mediated BoNT/D binding in both neurons and HEK293 cells. Furthermore, chimeric receptors containing the binding sites for BoNT/A and E, two other BoNTs that use SV2 as receptors, failed to mediate the entry of BoNT/D suggesting that BoNT/D binds SV2 via a mechanism distinct from BoNT/A and E. Finally, we demonstrated that gangliosides are essential for the binding and entry of BoNT/D into neurons and for its toxicity in vivo, supporting a double-receptor model for this toxin

Entering neurons: botulinum toxins and synaptic vesicle recycling

Botulinum toxins are metalloproteases that act inside nerve terminals and block neurotransmitter release through their cleavage of components of the exocytosis machinery. These toxins are used to treat human diseases that are characterized by hyperfunction of cholinergic terminals. Recently, evidence has accumulated that gangliosides and synaptic vesicle proteins cooperate to mediate toxin binding to the presynaptic terminal. The differential distribution of synaptic vesicle protein receptors, gangliosides and toxin substrates in distinct neuronal populations opens up the possibility of using different serotypes of botulinum toxins for the treatment of central nervous system diseases caused by altered activity of selected neuronal populations

High-Flexion Total Knee Replacement: Functional Outcome at One Year

Implants designed for enhanced flexion offer the prospect of improved function after total knee replacement (TKR). Whereas most studies evaluating these implants have focused on the range of knee flexion achieved, this study investigated the quality of function in deep knee flexion. The influences of residual pain and maximum flexion angle on function in deep knee flexion were also examined. Eighty-three patients (100 knees) were prospectively followed for 1 year after TKR with a rotating-platform posterior-stabilized high-flexion prosthesis. Range of motion was measured and Knee Society scores were calculated. A questionnaire evaluated residual knee pain and function in high-flexion activities. Mean Knee Society score was 95, and mean knee flexion was 125°, yet 20% of patients could neither kneel, nor squat, nor sit on their heels. Fifty-seven percent were able to kneel without significant difficulty; 69% were able to squat without significant difficulty; and 46% were able to sit on their heels without significant difficulty. Function in deep flexion correlated with pain scores but did not correlate with knee flexion angles or Knee Society scores. Results 1 year after TKR with a rotating-platform posterior-stabilized high-flexion prosthesis are encouraging, but one in five patients remain significantly limited in high-flexion activities

Anti-ganglioside antibodies in peripheral nerve pathology

Anti-ganglioside antibodies are principally associated with autoimmune peripheral neuropathies. In these disorders, immune attack is inadvertently directed at peripheral nerve by autoantibodies that target glycan structures borne by glycolipids, particularly gangliosides concentrated in nerve myelin and axons. The most thoroughly studied disorder is the acute paralytic disease, Guillain-Barré syndrome (GBS) in which IgG autoantibodies against gangliosides arise following acute infections, notably Campylobacter jejuni enteritis. Additionally, chronic autoimmune neuropathies are associated with IgM antibodies directed against many glycolipids including gangliosides. This introductory chapter briefly summarizes the immunological and pathological features of these disorders, focusing on the methodological development of antibody measurement and of animal models