Molecular neuropathology of TDP-43 proteinopathies

Abstract

The identification of TDP-43 as the major component of the pathologic inclusions in most forms of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS) resolved a long-standing enigma concerning the nature of the ubiquitinated disease protein under these conditions. Anti-TDP-43 immunohistochemistry and the recent development of novel tools, such as phosphorylation-specific TDP-43 antibodies, have increased our knowledge about the spectrum of pathological changes associated with FTLD-U and ALS and moreover, facilitated the neuropathological routine diagnosis of these conditions. This review summarizes the recent advances in our understanding on the molecular neuropathology and pathobiology of TDP-43 in FTLD and ALS.

Keywords: TDP-43; amyotrophic lateral sclerosis; frontotemporal dementia; molecular neuropathology.

Figure 1.

Neuropathology and biochemical alterations of TDP-43 in TDP-43-positive FTLD-U (“FTLD-TDP”). (a) TDP-43 immunohistochemistry labels cytoplasmic inclusions in dentate granule cells in FTLD-U. Note the dramatic loss of normal diffuse nuclear TDP-43 staining in inclusion-bearing cells. (b) Immunoblot analysis of sarcosyl-insoluble protein fractions from TDP-43-positive FTLD-U shows highly characteristic biochemical signature with pathological bands ~25 kDa (*), ~45 kDa (**) and a high molecular smear (***) in addition to the normal TDP-43 ~ 43 kDa.

Figure 2.

Distinct histological subtypes of TDP-43-positive FTLD-U (“FTLD-TDP”). Immunohistochemistry with antibody against TDP-43 showing the characteristic cortical inclusions in the distinct FTLD-TDP subtypes (numbering according to Sampathu et al. [12]).

Figure 3.

ALS associated mutations in TDP-43. Schematic diagram of TDP-43 with characteristic functional domains of TDP-43 and sites of identified mutations in familial (fALS) and sporadic (sALS) amyotrophic lateral sclerosis. Abbreviations: RRM, RNA recognition motif; NLS: nuclear localization sequence; NES, nuclear export sequence.