Expansion of polyglutamine repeat in huntingtin leads to abnormal protein interactions involving calmodulin.

Huntington's disease (HD) is an inherited neurodegenerative disorder associated with expansion of a CAG repeat in the IT15 gene. The IT15 gene is translated to a protein product termed huntingtin that contains a polyglutamine (polyGln) tract. Recent investigations indicate that the cause of HD is expansion of the polyGln tract. However, the function of huntingtin and how the expanded polyGln tract causes HD is not known. We investigate potential protein-protein interactions of huntingtin using affinity resins. Huntingtin from brain extracts is retained on calmodulin(CAM)-Sepharose in a calcium-dependent fashion. We purify rat huntingtin to apparent homogeneity using a combination of DEAE-cellulose column chromatography, ammonium sulfate precipitation, and preparative SDS/PAGE. Purified rat huntingtin does not interact with CAM directly as revealed by 125I-CAM overlay. Huntingtin forms a large CAM-containing complex of over 1,000 kDa in the presence of calcium, which partially disassociates in the absence of calcium. Furthermore, an increased amount of mutant huntingtin from HD patient brains is retained on CAM-Sepharose compared to normal huntingtin from control patient brains, and the mutant allele is preferentially retained on CAM-Sepharose in the absence of calcium. These results suggest that huntingtin interacts with other proteins including CAM and that the expansion of polyGln alters this interaction.

Mutations in the MSH3 gene preferentially lead to deletions within tracts of simple repetitive DNA in Saccharomyces cerevisiae.

Eukaryotic genomes contain tracts of DNA in which a single base or a small number of bases are repeated (microsatellites). Mutations in the yeast DNA mismatch repair genes MSH2, PMS1, and MLH1 increase the frequency of mutations for normal DNA sequences and destabilize microsatellites. Mutations of human homologs of MSH2, PMS1, and MLH1 also cause microsatellite instability and result in certain types of cancer. We find that a mutation in the yeast gene MSH3 that does not substantially affect the rate of spontaneous mutations at several loci increases microsatellite instability about 40-fold, preferentially causing deletions. We suggest that MSH3 has different substrate specificities than the other mismatch repair proteins and that the human MSH3 homolog (MRP1) may be mutated in some tumors with microsatellite instability.

Kitāb Soḥbat ōrang ber-dōsa: [The friend of sinners; a collection of pious tracts in the Malay language]

Lithographed.

Tracts for computers.

Mode of access: Internet.

The Scholar armed against the errors of the time ; or, A collection of tracts on the principles and evidences of Christianity, the constitution of the Church, and the authority of civil government ... /

Edited by William Jones. Cf. Halkett & Laing.

Land areas : or, How to calculate and verify contents of tracts of land /

Mode of access: Internet.

Later Stuart tracts,

Most of the tracts have special title-pages.

Tracts issued by the Marriage Law Defence Union.

Mode of access: Internet.

The cases of polygamy, concubinage, adultery, divorce, &c. seriously and learnedly discussed. : Being a compleat collection of all the remarkable tryals and tracts which have been written on those important subjects. /

Reissued 1736 with title: Select and curious cases of polygamy.

Census tracts : 1980 census of population and housing.

Issued May 1983-

Bibliotheca gloucestrensis: a collection of scarce and curious tracts relating to the county and city of Gloucester, illustrative of, and published during the civil war, with biographical and historical remarks /

Each tract has reprint of original t.p.

Tracts. : no. I-IV.

I. Income and expenditure. Method of keeping the public accounts The national debt.--II. The war establishment.--III. The civil government.--IV. Miscellaneous estimates.

Tracts

No. 9, 11-12, 2nd ed. ; no. 10, 3rd ed.

Sixteenth census of the United States: 1940. Population and housing. Statistics for census tracts ...

Typed title-page.