TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: protein misfolding diseases without amyloidosis.

H erein, 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. Arch Neurol. 2007;64(10):1388-1394