KIF1A is a kinesin family motor involved in the axonal transport of synaptic vesicle precursors (SVPs) along microtubules (MTs). In humans, more than 10 point mutations in KIF1A are associated with the motor neuron disease hereditary spastic paraplegia (SPG). However, not all of these mutations appear to inhibit the motility of the KIF1A motor, and thus a cogent molecular explanation for how KIF1A mutations lead to neuropathy is not available. In this study, we established in vitro motility assays with purified full-length human KIF1A and found that KIF1A mutations associated with the hereditary SPG lead to hyperactivation of KIF1A motility. Introduction of the corresponding mutations into the Caenorhabditis elegans KIF1A homolog unc-104 revealed abnormal accumulation of SVPs at the tips of axons and increased anterograde axonal transport of SVPs. Our data reveal that hyperactivation of kinesin motor activity, rather than its loss of function, is a cause of motor neuron disease in humans.axonal transport | hereditary spastic paraplegia | kinesin | KIF1A | UNC-104

APP associates with kinesin-1 via JIP1. In JIP1-decicient neurons, the fast velocity and high frequency of anterograde transport of APP cargo are impaired to reduced velocity and lower frequency, respectively. Interaction of JIP1 with KLC via two novel elements in JIP1 plays an important role in efficient APP axonal transport.

Nucleophilic substitution 1,3-Diaryltetrazolium salts 5 and 6 have been prepared by nitric acid oxidation of the corresponding 5-thiolates 4. The reaction of 5 with mercury(I1) acetate gives (1,3-diaryltetrazolylene)mercury(II) complexes ?, which provide 5-halotetrazolium salts 8-10 by treatment with halogen. 1,3-Diphenyltetrazolylene (16), generated in situ by proton abstraction of 1,3-diphenyltetrazolium salts 5 a or 6a, has been trapped with p-(dimethy1amino)benenediazonium tetrafluoroborate to form 18/18'. The palladium(I1) complex 19 of 1,3-diphenyltetrazolylene has been prepared by oxidative addition of tetrakis(triphenylphosphane)palladium(O) to 5-chlorotetrazolium salt 8. The reactivity of various 5-substituted tetrazolium salts toward carbon nucleophiles depends on the nature of the substituents at C-5. With electronegative substituents, nucleophilic substitution proceeds at C-5, whereas electron-donating substituents direct the nucleophiles towards N-2 yielding ring-cleaved products.Mesoionic compounds of type 1 are an interesting family of heterocycles because of their unique structure, reaction behaviour, and biological activities. A number of mesoionic compounds have hitherto been prepared and extensively studied"'. Heterocyclic cations 2 derived from 1, where its exocyclic anionic group (f) has been replaced by hydrogen, are expected to be of synthetic value as precursors to mesoionic systems with different exocyclic groups. Cations 2 are also interesting as the conjugate acids of heterocyclic carbenes 3. The latter are particularly intriguing molecules, since an aromatic canonical form is expected to contribute to its ground-state electronic structure, and hence compounds 3 are expected to behave as aromatic carbenes. As an example of such mesoionic carbenes, Weiss has recently reported on the generation of 2,3-diaryltetrazolylenes by deprotonation of the corresponding tetrazolium salts and has discussed their properties[". As a part of our work on mesoionic tetrazolium corn pound^'^^, we describe in this paper the preparation of 1,3-diaryltetrazolium salts and their transformations to various 5-substituted derivatives. 1,3-Diaryltetrazolium mesoionic compounds belong to type A mesoions, whereas Weiss's 2,3-diaryl isomers are examples of type B mesoionic compounds [']. SynthesisWhen mesoionic thiolates['"I and selenolate~[~' are dissolved in conc. nitric acid, they are converted to the corresponding heterocyclic cations with loss of the exocyclic sulfur and selenium. This has been found to be also the case for 1,3-diaryltetrazolium-5-thiolates (4), and 1,3-diaryltetrazolium salts are isolated in good yields as stable tetrafluoroborates 5. The corresponding tetraphenylborate 6 a is obtained by anion exchange of 5a with sodium tetraphenylborate. Mercuration of tetrazolium salt 5 with mercury(I1) acetate proceeds smoothly in dimethyl sulfoxide (DMSO) at 100°C to give bis(tetrazolio)mercury(II) 7, whose protolysis with conc. hydrochloric acid gives back 5. Replacement of the mercury atom of 7 by halog...

No abstract