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.)
- Perissinotti PP, Martínez-Hernández E, He Y, Koob MD, Piedras-Rentería ES. Genetic deletion of KLHL1 leads to hyperexcitability in hypothalamic POMC neurons and lack of electrical responses to leptin. Front Neurosci. 2021 Sep 9;15:718464.
- Castro M, Venkateswaran N , Peters ST, Deyle DR, Bower M, Koob MD, Boeve BF, Vossel K. Case Report: Early-onset behavioral variant frontotemporal dementia in patient with retrotransposed full-length transcript of matrin-3 variant 5. Front Neurol. 2020 Dec 21;11:600468.
- Martínez-Hernández E, Zeglin A, Almazan E, Perissinotti P, He Y, Koob M, Martin JL, Piedras-Rentería ES. KLHL1 controls CaV3.2 expression in DRG neurons and mechanical sensitivity to pain. Front Mol Neurosci. 2020 Jan 8;12:315.
- 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 May;46:15-21.
- 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.
Former Graduate Students:
Julia Gamache (Ph.D. 2019, Neuroscience, University of Minnesota)