The discovery of mutations in C9ORF72 as a cause of both FTLD and ALS provides a clear link between these two degenerative diseases and suggests that they form a clinicopathologic disease spectrum. Research on C9ORF72 related neurodegenerative disorders, thus, holds promise to unlock secrets related to this disease spectrum. Postmortem neuropathology plays an important role in establishing the range of pathology in both ALS and FTLD, as well as documenting other disease processes that may have contributed to the clinical syndrome. As animal models are developed to study disease pathogenesis of ALS and FTLD, neuropathologic studies are increasingly important to monitor outcomes of experimental manipulations and for comparison to human disorders. Core C participates in these activities as well as providing tissue samples to investigators obtain from postmortem studies. Core C will work closely with clinical coordinators to obtain rapid autopsies of patients enrolled in clinical studies in Core B. In addition to brain and spinal cord, tissue samples will also be obtained from skeletal muscle, peripheral nerve and the internal organs. Core C will bank these fixed and frozen tissue specimens and process them for histologic studies. Core C will provide diagnostic evaluations. Core C will provide tissue samples for genetic studies, basic research, and clinicopathologic studies in Projects 1, 2 and 3, respectively. Core C will provide technical support to Projects 2 and 3 with respect to neurohistology of human and animal brains.
The specific aims of the core are as follows:
Specific Aim 1. For enrolled subjects in the deeded autopsy program who die during the course of the project, conduct autopsies to harvest brain, spinal cord, skeletal muscle and peripheral nerve, as well as samples from internal organs, with a portion of each sample frozen for subsequent research and another portion preserved in fixative for diagnostic evaluation and for future research studies. A neuropathologic diagnostic evaluation will be performed on each case using a standardized protocol. Upon completion of the diagnostic evaluation, reports will be entered into the electronic medical record and copies will be sent to the next-of-kin along with an explanatory letter in lay person terms.
Specific Aim 2. Process and assist in the neuropathologic characterization of mouse brains from Project 2, and assist with characterizing antibodies generated in Project 2.
Specific Aim 3. Provide tissue samples to Projects 1, 2 and 3 as well as to qualified investigators at other institutions. Core C will facilitate research in the program project, but also contribute to medical education, physician quality control, and feedback to families whose relatives were engaged in research on ALS and FTLD.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Mayo Clinic Jacksonville
United States
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Zhang, Yong-Jie; Jansen-West, Karen; Xu, Ya-Fei et al. (2014) Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol 128:505-24
Su, Zhaoming; Zhang, Yongjie; Gendron, Tania F et al. (2014) Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron 83:1043-50