The Neuropathology and Optical 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 (DMI 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 the Projects 1 and 2 using mouse models by providing histological services 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 Optical 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 use stimulants to counteract hypersomnolence, 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. These correlations are similar to the resting state fMRI observed in humans and are linked to cognitive function. Therefore, the Core 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.
|Nakamori, Masayuki; Hamanaka, Kohei; Thomas, James D et al. (2017) Aberrant Myokine Signaling in Congenital Myotonic Dystrophy. Cell Rep 21:1240-1252|
|Cleary, John Douglas; Ranum, Laura Pw (2017) New developments in RAN translation: insights from multiple diseases. Curr Opin Genet Dev 44:125-134|
|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|
|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|
|Taliaferro, J Matthew; Vidaki, Marina; Oliveira, Ruan et al. (2016) Distal Alternative Last Exons Localize mRNAs to Neural Projections. Mol Cell 61:821-33|
|Freyermuth, Fernande; Rau, Frédérique; Kokunai, Yosuke et al. (2016) Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy. Nat Commun 7:11067|
|Scotti, Marina M; Swanson, Maurice S (2016) RNA mis-splicing in disease. Nat Rev Genet 17:19-32|
|Hewitt, Angela L; Popa, Laurentiu S; Ebner, Timothy J (2015) Changes in Purkinje cell simple spike encoding of reach kinematics during adaption to a mechanical perturbation. J Neurosci 35:1106-24|
|Goodwin, Marianne; Mohan, Apoorva; Batra, Ranjan et al. (2015) MBNL Sequestration by Toxic RNAs and RNA Misprocessing in the Myotonic Dystrophy Brain. Cell Rep 12:1159-68|
|Coram, Ryan J; Stillwagon, Samantha J; Guggilam, Anuradha et al. (2015) Muscleblind-like 1 is required for normal heart valve development in vivo. BMC Dev Biol 15:36|
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