The Neuropathology and Functional Imaging Core will provide neuropathological and physiological services focused on the evaluation of both patients with myotonic dystrophy and mouse models of the disease. The Neuropathology component will provide neuropathological characterization of patients who have died with myotonic dystrophy types 1 and 2 (DM1 and DM2). The objective is to define the distribution and nature of the neuropathological alterations associated with DM1 and DM2, with a particular emphasis on correlation with antemortem neuroimaging and/or clinical CNS-related deficits in patients who have been studied in Project 3. The Core will aid investigators in Projects 1 and 2 by providing histological services and tissues with a major focus on correlating the neuropathological findings in the transgenic mouse models with those of the corresponding human diseases to understand pathological mechanisms. The Functional Imaging component of the Core will provide functional assessments of the cerebral cortical circuitry in the mouse models developed by Projects 1 and 2 and test in the mouse models for abnormalities identified in DM patients by Project 3. The Core will use optical imaging and single cell electrophysiological recordings to characterize the cerebral cortical circuitry in vivo. As DM patients have exaggerated sensitivity to sedatives and stimulants, the Core will investigate whether cerebral cortical circuits show altered sensitivity to these drugs. Flavoprotein imaging has revealed correlations in the background fluorescence among different regions in the cerebral cortex that can be used to assess functional connectivity. The alterations in white matter integrity and grey matter in DM is likely to result in changes in functional connectivity. Therefore, Core A will also test whether this functional connectivity in the cerebral cortex is abnormal in the DM mouse models. Finally, Projects 1 and 2 are proposing to develop mouse models with the goal of reversing the disease phenotypes. Having defined specific circuit abnormalities in the cerebral cortex, the Core will evaluate if the abnormalities are corrected in these rescue mouse models.
Myotonic dystrophy is a complex neurodegenerative disorder that affects multiple systems in the body. Patients have significant neurological problems. However, there is little known about how the disease affects the central nervous system. This proposal aims to understand the underlying disease mechanisms and the nervous system changes in this poorly understood disorder.
|Pattamatta, Amrutha; Cleary, John D; Ranum, Laura P W (2018) All in the Family: Repeats and ALS/FTD. Trends Neurosci 41:247-250|
|Sznajder, ?ukasz J; Thomas, James D; Carrell, Ellie M et al. (2018) Intron retention induced by microsatellite expansions as a disease biomarker. Proc Natl Acad Sci U S A 115:4234-4239|
|Chen, Gang; Carter, Russell E; Cleary, John D et al. (2018) Altered levels of the splicing factor muscleblind modifies cerebral cortical function in mouse models of myotonic dystrophy. Neurobiol Dis 112:35-48|
|Cleary, John Douglas; Pattamatta, Amrutha; Ranum, Laura P W (2018) Repeat-associated non-ATG (RAN) translation. J Biol Chem 293:16127-16141|
|Nakamori, Masayuki; Hamanaka, Kohei; Thomas, James D et al. (2017) Aberrant Myokine Signaling in Congenital Myotonic Dystrophy. Cell Rep 21:1240-1252|
|Zu, Tao; Cleary, John D; Liu, Yuanjing et al. (2017) RAN Translation Regulated by Muscleblind Proteins in Myotonic Dystrophy Type 2. Neuron 95:1292-1305.e5|
|Thomas, James D; Sznajder, ?ukasz J; Bardhi, Olgert et al. (2017) Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy. Genes Dev 31:1122-1133|
|Cleary, John Douglas; Ranum, Laura Pw (2017) New developments in RAN translation: insights from multiple diseases. Curr Opin Genet Dev 44:125-134|
|Grima, Jonathan C; Daigle, J Gavin; Arbez, Nicolas et al. (2017) Mutant Huntingtin Disrupts the Nuclear Pore Complex. Neuron 94:93-107.e6|
|Moloney, Christina; Rayaprolu, Sruti; Howard, John et al. (2016) Transgenic mice overexpressing the ALS-linked protein Matrin 3 develop a profound muscle phenotype. Acta Neuropathol Commun 4:122|
Showing the most recent 10 out of 57 publications