We have identified trinucleotide mutations that cause two forms of spinocerebellar ataxia, SCA7 and SCA8, and are focusing our efforts on characterizing at the molecular level the genes involved in SCA8. The CTG trinucleotide expansion mutation that causes SCA8 is in an antisense RNA that appears to be involved in the regulation of another transcript that encodes a brain-specific protein we have called Kelch-like 1 (KLHL1). We are studying the interaction of these two RNAs as well as the molecular properties and functions of the KLHL1 protein using mouse, zebrafish, Drosophila, and tissue culture models.
Our results to date indicate that KLHL1 is an actin-organizing molecule that is specifically expressed in a variety of neurons in the brain, and is localized to the cell body and dendrites of these cells. We have recently found that mice in which we over-express the endogenous KLHL1-antisense RNA develop a pronounced hyperactive, circling phenotype indicative of defects in neurons in the basal ganglia. We are currently characterizing both this model and a mouse model in which we have deleted the KLHL1 sense and antisense genes.
(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
- Gamache JE, Kemper L, Steuer E, Leinonen-Wright K, Choquette JM, Hlynialuk C, Benzow K, Vossel KA, Xia W, Koob MD, Ashe KH. Developmental pathogenicity of 4-repeat human tau is lost with the P301L mutation in genetically matched tau-transgenic mice. J Neurosci. 2020;40(1):220-236.
- Gamache JE, Benzow K, Forster C, Kemper L, Hlyniakluk C, Furrow E, Ashe KH, Koob MD. Factors other than hTau overexpression that contribute to tauopathy-like phenotype in rTg4510 mice. Nat Commun. 2019;10:2479.
- Yoon YG, Koob MD. Intramitochondrial transfer and engineering of mammalian mitochondrial genomes in yeast. Mitochondrion. 2019 Apr 10. pii: S1567-7249(18)30037-0.
- Perissinotti PP, Ethington EA, Almazan E, Martínez-Hernández E, Kalil J, Koob MD, Piedras-Rentería ES. Calcium current homeostasis and synaptic deficits in hippocampal neurons from Kelch-like 1 knockout mice. Front Cell Neurosci. 2015 Jan 7;8:444.
- Perissinotti PP, Ethington EG, Cribbs L, Koob MD, Martin J, Piedras-Rentería ES. Down-regulation of endogenous KLHL1 decreases voltage-gated calcium current density. Cell Calcium. 2014;55:269-280.
- Benzow KA, Koob MD. Markerless modification of trinucleotide repeat loci in BACs. Methods Mol Biol. 2013;1010:265-76
- Yang YW, Koob MD. Transferring isolated mitochondria into tissue culture cells. Nucleic Acids Res. 2012;40(19):e148.
- Yoon YG, Yang YW, Koob MD. PCR-based cloning of the complete mouse mitochondrial genome and stable engineering in Escherichia coli. Biotechnol Lett. 2009;31:1671-1676.
- Yoon YG, Koob MD. Selection by drug resistance proteins located in the mitochondria of mammalian cells. Mitochondrion. 2008;8(5-6):345-351.
- Yoon YG, Haug CL, Koob MD. Interspecies mitochondrial fusion between mouse and human mitochondria is rapid and efficient. Mitochondrion. 2007;7:223-229
- Aromolaran KA, Benzow KA, Koob MD, Piedras-Rentería ES. The Kelch-like protein 1 modulates P/Q-type calcium current density. Neuroscience. 2007;145:841-850.
Former Graduate Students:
Julia Gamache (Ph.D. 2019, Neuroscience, University of Minnesota)