TDP-43 Proteinopathy in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis

“…25 Mutations in MAPT, the gene that encodes tau, the protein component of neurofibrillary tangles, cause some cases of FTD without ubiquinated TDP-43 deposits. 26 Thus, TARDBP is an obvious candidate gene for FALS and other familial FTD syndromes not caused by MAPT or progranulin mutations. It is not surprising therefore, that while this manuscript was in preparation, several mutations in TARDBP were identified in ALS cases by two groups, though no associated neuropathology has been reported.…”

Targeted Depletion of TDP-43 Expression in the Spinal Cord Motor Neurons Leads to the Development of Amyotrophic Lateral Sclerosis-like Phenotypes in Mice

“…TDP-43 molecules in the diseased cells of the patient brains or spinal cords are characterized by abnormal ubiquitination, hyperphosphorylation, and partial cleavage to generate ϳ25-kDa and 35-kDa C-terminal fragment(s). Furthermore, TDP-43 is partially or completely cleared from the nuclei of either neuronal or glial cells containing the TDP-43(ϩ) and ubiquitin(ϩ) aggregates/inclusions, or UBIs, in the cytoplasm (18).…”

The self-interaction of native TDP-43 C terminus inhibits its degradation and contributes to early proteinopathies

“…T he aggregation of misfolded, phosphorylated, ubiquitinated C-terminal fragments of TAR DNA-binding protein 43 (TDP-43) is a common characteristic in frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis (ALS) [1][2][3][4][5][6][7][8] . Among mammals, zebrafish and flies, the protein sequence, biochemical properties and biological functions of TDP-43 are well conserved.…”