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Probing the Role of an Intermediate State in TDP‐43: A Gateway to Developing New Biomarkers and Therapies for Neurodegenerative Disease
Author(s) -
Mackness Brian,
Tran Meme,
Deveau Laura,
AvendanoVazquez Selma,
Matthews Robert,
Bilsel Osman,
Massi Francesca,
Zitzewitz Jill
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.882.10
Subject(s) - frontotemporal lobar degeneration , protein folding , neurodegeneration , context (archaeology) , chemistry , protein aggregation , folding (dsp implementation) , biophysics , computational biology , microbiology and biotechnology , neuroscience , biochemistry , biology , disease , medicine , frontotemporal dementia , pathology , dementia , paleontology , electrical engineering , engineering
Pathological alteration of TDP‐43 is a hallmark feature of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Fragments, comprised of the second RNA recognition motif (RRM2) and the disordered C‐terminus, have been observed in cytoplasmic inclusions, suggesting that conformational changes within these regions play a role in aggregation and toxicity. Circular dichroism and fluorescence spectroscopies reveal a three‐state equilibrium unfolding model for RRM2 with a partially‐folded intermediate state. This state likely plays a biological role by enhancing access to the nuclear export signal (NES) contained within RRM2; however, it may also serve as a molecular hazard linking productive folding and function with pathological misfolding and aggregation. Structural insights using nuclear magnetic resonance, small‐angle X‐ray scattering and mutational analysis have shown the intermediate is unfolded‐like with potential residual structure in the N‐terminus of RRM2. These results suggest that the NES may be unfolded in this state for recognition by the export machinery. Ongoing fluorescence correlation spectroscopy and cellular‐based studies will investigate how this intermediate state, in the context of the disordered C‐terminus, may disrupt normal folding and function to enhance misfolding and toxicity. These insights will provide essential information for designing therapeutic strategies targeting the RRM2 intermediate state for preventing TDP‐43 dysfunction and aggregation in a set of neurodegenerative diseases.