TY - JOUR
T1 - Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction
AU - Cannon, Ashley
AU - Yang, Baoli
AU - Knight, Joshua
AU - Farnham, Ian M.
AU - Zhang, Yongjie
AU - Wuertzer, Charles A.
AU - D'Alton, Simon
AU - Lin, Wen Lang
AU - Castanedes-Casey, Monica
AU - Rousseau, Linda
AU - Scott, Brittany
AU - Jurasic, Michael
AU - Howard, John
AU - Yu, Xin
AU - Bailey, Rachel
AU - Sarkisian, Matthew R.
AU - Dickson, Dennis W.
AU - Petrucelli, Leonard
AU - Lewis, Jada
N1 - Funding Information:
Acknowledgments We thank Virginia Phillips, Sarah Miles, Brittany Dugger, Melissa Murray, and Jennifer Gass for technical support. We thank David Borchelt for helpful discussions. This work was supported by the American Federation for Aging Research Affiliate Research Grant Program (Y.Z.), National Institutes of Health/ National Institute on Aging [P50AG16574 (D.W.D.); R01AG026251 and R01AG026251–03A2 (L.P.); and P01-AG17216-08 (L.P., D.W.D.)], National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01 NS 063964-01 (L.P.), 5R21NS071097-02 (J.L.)], Amyotrophic Lateral Sclerosis Association (L.P. and J.L.), and Department of Defense [USAMRMC PR080354 (L.P. and J.L.)], Mayo Clinic (D.W.D, L.P., and J.L.), McKnight Brain Research Foundation and the Evelyn F. and William L. McKnight Brain Institute at the University of Florida (M.R.S.), and University of Florida (J.L.).
PY - 2012/6
Y1 - 2012/6
N2 - Ubiquitin-immunoreactive neuronal inclusions composed of TAR DNA binding protein of 43 kDa (TDP-43) are a major pathological feature of frontotemporal lobar degeneration (FTLD-TDP). In vivo studies with TDP-43 knockout mice have suggested that TDP-43 plays a critical, although undefined role in development. In the current report, we generated transgenic mice that conditionally express wild-type human TDP-43 (hTDP-43) in the fore-brain and established a paradigm to examine the sensitivity of neurons to TDP-43 overexpression at different developmental stages. Continuous TDP-43 expression during early neuronal development produced a complex phenotype, including aggregation of phospho-TDP-43, increased ubiquitin immunoreactivity, mitochondrial abnormalities, neurodegeneration and early lethality. In contrast, later induction of hTDP-43 in the forebrain of weaned mice prevented early death and mitochondrial abnormalities while yielding salient features of FTLD-TDP, including progressive neurodegeneration and ubiquitinated, phospho-TDP-43 neuronal cytoplasmic inclusions. These results suggest that neurons in the developing forebrain are extremely sensitive to TDP-43 overexpression and that timing of TDP-43 over-expression in transgenic mice must be considered when distinguishing normal roles of TDP-43, particularly as they relate to development, from its pathogenic role in FTLD-TDP and other TDP-43 proteinopathies. Finally, our adult induction of hTDP-43 strategy provides a mouse model that develops critical pathological features that are directly relevant for human TDP-43 proteinopathies.
AB - Ubiquitin-immunoreactive neuronal inclusions composed of TAR DNA binding protein of 43 kDa (TDP-43) are a major pathological feature of frontotemporal lobar degeneration (FTLD-TDP). In vivo studies with TDP-43 knockout mice have suggested that TDP-43 plays a critical, although undefined role in development. In the current report, we generated transgenic mice that conditionally express wild-type human TDP-43 (hTDP-43) in the fore-brain and established a paradigm to examine the sensitivity of neurons to TDP-43 overexpression at different developmental stages. Continuous TDP-43 expression during early neuronal development produced a complex phenotype, including aggregation of phospho-TDP-43, increased ubiquitin immunoreactivity, mitochondrial abnormalities, neurodegeneration and early lethality. In contrast, later induction of hTDP-43 in the forebrain of weaned mice prevented early death and mitochondrial abnormalities while yielding salient features of FTLD-TDP, including progressive neurodegeneration and ubiquitinated, phospho-TDP-43 neuronal cytoplasmic inclusions. These results suggest that neurons in the developing forebrain are extremely sensitive to TDP-43 overexpression and that timing of TDP-43 over-expression in transgenic mice must be considered when distinguishing normal roles of TDP-43, particularly as they relate to development, from its pathogenic role in FTLD-TDP and other TDP-43 proteinopathies. Finally, our adult induction of hTDP-43 strategy provides a mouse model that develops critical pathological features that are directly relevant for human TDP-43 proteinopathies.
KW - Amyotrophic lateral sclerosis
KW - Apoptosis
KW - Frontotemporal lobar degeneration
KW - Neurodevelopment
KW - TDP-43
KW - Transgenic mice
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UR - http://www.scopus.com/inward/citedby.url?scp=84866423602&partnerID=8YFLogxK
U2 - 10.1007/s00401-012-0979-3
DO - 10.1007/s00401-012-0979-3
M3 - Article
C2 - 22539017
AN - SCOPUS:84866423602
SN - 0001-6322
VL - 123
SP - 807
EP - 823
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 6
ER -