trends in CELL BIOLOGY (Vol. 9) March 1999 119

meeting report

Gloria Lee,University of IowaCollege ofMedicine, IowaCity, IA 52242USA.E-mail: Gloria-Lee@mail.int-med.uiowa.edu

Tau protein inneurodegenerative disease

Organizer: Gloria Lee, University ofIowa College of Medicine, IA, USA.

This year, the idea that the micro-tubule-associated protein tau plays adirect role in neurodegenerative dis-eases has received a boost from thediscovery that mutations in the geneencoding tau are linked to an auto-somal–dominant neurodegenerativedisease, frontotemporal dementiawith parkinsonism linked to chromo-some 17. This meeting served as aforum to discuss the mechanismsthrough which the mutations cancause neurodegeneration. Amongthe hypotheses proposed at thismeeting were: • tau missense mutations attenuate

microtubule binding such that, over

time, overall microtubule stability isdecreased, leading to the loss ofneuronal cell structure and function(V. M. Y. Lee, Philadelphia, USA);

• mutations in tau splicing upregulatetau isoforms that are more effi-ciently assembled into filaments,with assembly facilitated by fattyacids in the membrane, thereby creating abnormal toxic filaments in membrane-proximal regions(L. I. Binder, Chicago, USA);

• tau missense mutations affect thephysical conformation of tau, therebyallowing the gain of pathogenicfunctions that might not involvemicrotubules (P. Davies, Bronx, USA). The recently described role for tau

in intracellular transport (E. M.Mandelkow, Hamburg, Germany) andthe interaction between tau and Src-family non-receptor tyrosine kinases(G. Lee, Iowa City, USA) could also

provide means by which abnormalitiesin tau affect neuronal viability. A highpriority for investigators is the develop-ment of a mammalian animal systemcapable of forming abnormal tau fila-ments. Data presented regarding thenature of tau filaments assembledin vitro and in the sea lamprey(H. Ksiezak-Reding, Bronx, USA;L. Kohlstaedt, Santa Barbara, USA; andG. Hall, Lowell, USA) continue toinvestigate the relationship betweenthese filaments and the abnormal taufilaments from diseased brain. While itis early days for investigations of thefunctional consequences of the taumutations, and new tau mutations arestill being identified, it is clear that theelucidation of the molecular mecha-nisms leading to neurodegenerationwill offer potential targets for thera-peutic intervention to slow the progression of the disease.

Are there multiple roles for theRan GTPase?

Organizers: Mary Dasso, NationalInstitute of Child Health and HumanDevelopment, Bethesda, USA; andShelley Sazer, Baylor College ofMedicine, Houston, USA.

The Ran GTPase is required fornuclear transport. However, Ran-pathway mutants cause diverse phe-notypes, not all of which can be eas-ily linked to nuclear trafficking. Thissession examined the spectrum ofRan-dependent processes. P. Lavia(Rome, Italy) demonstrated thatRanBP1 is regulated during the cellcycle. RanBP1 overexpression or mis-localization causes defects in chromo-some condensation and mitotic pro-gression. P. Kalab (Bethesda, USA)demonstrated that Ran regulatesassembly of the mitotic spindle in

Xenopus egg extracts in a nuclear-transport-independent manner.Moreover, increasing the GTP–Ran toGDP–Ran ratio dramatically altersmicrotubule dynamics, causing theassembly of aster-like structures evenin the absence of chromosomes.T. Nishimoto (Fukuoka, Japan) dis-cussed a possible effector of the activ-ity of Ran in spindle assembly –RanBPM. RanBPM is a centrosomalprotein that interacts with GTP–Ranin two-hybrid assays. Antibodiesagainst RanBPM prevent aster assem-bly on centrosomes in vitro and inXenopus extracts. S. Sazer (Houston,USA) showed that Ran-pathwaymutants disrupt nuclear envelopeintegrity, septum formation andchromosome condensation inSchizosaccharomyces pombe. Theseseptation defects were rescued byoverexpression of Imp2p, a proteinthat localizes to the medial ring

during septation and that appears to regulate medial ring destabilization.C. Merrill (Madison, USA) showedthat RanGAP1 is mutated inDrosophila with the SegregationDistorter (SD) phenotype. Themutated RanGAP1 protein mislocal-izes during spermatogenesis and actsin a dominant manner to disrupt mat-uration of sperm with particular al-leles of the responder (Rsp) gene.K. Welch (Charlottesville, USA) dis-cussed the role of the NTF2 protein inmaintaining the nuclear gradient ofGTP–Ran during interphase. M. Rush(New York, USA) discussed the capac-ity of Ran mutants to disrupt nuclearassembly in Xenopus egg extracts.Together, these presentationsdemonstrated that the regulation ofthe Ran pathway is likely to be morecomplex than has been previouslyimagined and that its effectors are farfrom fully understood.

Mary Dasso,National Instituteof Child Healthand HumanDevelopment,Bethesda, USA.E-mail: mdasso@helix.nih.gov

g-Tubulin: questionsoutstanding

Organized by P. G. Wilson, Universityof Wisconsin-Madison, USA.

Microtubules are polarized filamentsof a- and b-tubulin heterodimers thatprovide structure and organization to eukaryotic cells. g-Tubulin hasemerged as a key player in organiz-ation of microtubules at centrosomes,and our subgroup assembled to discuss why this is the case. a- and b-tubulins are highly conserved,

presumably reflecting the sensitivity ofmicrotubule polymerization to tubulinstructure, but g-tubulins can showextensive amino acid sequence diver-sity. A structural model of human g-tubulin revealed that g-tubulins areunlikely to form protofilaments thatare similar to those formed by dimersof a- and b-tubulin, although somekind of longitudinal interactionbetween g-tubulins is likely(E. Nogales, Berkeley, USA). g-Tubulin,together with at least two other con-served centrosomal proteins, forms aring-shaped complex in higher

eukaryotes (Y. Zheng, Baltimore, USA;R. Jeng, Stanford, USA). Tomographicreconstructions of Drosophila g-tubu-lin complexes revealed a hollowdome-like structure (V. Guenebaut,San Francisco, USA), consistent with aring of g-tubulins capped by subunitsof higher molecular mass. Rather thanthe 13-protofilament numberexpected of a centrosome-boundtemplate, microtubules formed athigh tubulin concentrations in thepresence and absence of these com-plexes showed a protofilament num-ber from 11 to 16, centering on 14.