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Protein Misfolding Diseases Without Amyloidosis

Manuela Neumann, MD; Linda K. Kwong, PhD; Deepak M. Sampathu, PhD; John Q. Trojanowski, MD, PhD; Virginia M.-Y. Lee, PhD, MBA

Arch Neurol. 2007;64(10):1388-1394.

Herein, we review advances in understanding a group of disorders collectively known as TAR-DNA binding protein 43 (TDP-43) proteinopathies since the report that TDP-43 is the major disease protein that mechanistically links frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) with and without motor neuron disease to amyotrophic lateral sclerosis. Because TDP-43 proteinopathy underlies sporadic and familial forms of FTLD-U and amyotrophic lateral sclerosis, they may share similar mechanisms linked to the abnormal hyperphosphorylation, ubiquitination, and cleavage of pathologic TDP-43 to generate C-terminal fragments in brain and spinal cord affected with FTLD-U and amyotrophic lateral sclerosis. TDP-43 proteinopathies are distinct from most other neurodegenerative disorders in which protein misfolding leads to brain amyloidosis, as pathologic TDP-43 forms neuronal and glial inclusions lacking the features of brain amyloid deposits. We discuss the implications of these distinct aspects of TDP-43 proteinopathies for developing better diagnostics and therapeutics for FTLD-U and amyotrophic lateral sclerosis.

Author Affiliations: Center for Neuropathology and Prion Research, Ludwig Maximilians University of Munich, Munich, Germany (Dr Neumann); and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine and Institute on Aging (Drs Kwong, Sampathu, Trojanowski, and Lee), University of Pennsylvania School of Medicine, Philadelphia.

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