ALS and FTLD: two faces of TDP-43 proteinopathy

Abstract

Major discoveries have been made in the recent past in the genetics, biochemistry and neuropathology of frontotemporal lobar degeneration (FTLD). TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the major pathological protein of FTLD with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Recently, mutations in the TARDBP gene in familial and sporadic ALS have been reported which demonstrate that abnormal TDP-43 alone is sufficient to cause neurodegeneration. Several familial cases of FTLD-U, however, are now known to have mutations in the progranulin (GRN) gene, but granulin is not a component of the TDP-43- and ub-ir inclusions. Further, TDP-43 is found to be a component of the inclusions of an increasing number of neurodegenerative diseases. Other FTLD-U entities with TDP-43 proteinopathy include: FTLD-U with valosin-containing protein (VCP) gene mutation and FTLD with ALS linked to chromosome 9p. In contrast, chromosome 3-linked dementia, FTLD-U with chromatin modifying protein 2B (CHMP2B) mutation, has ub-ir, TDP-43-negative inclusions. In summary, recent discoveries have generated new insights into the pathogenesis of a spectrum of disorders called TDP-43 proteinopathies including: FTLD-U, FTLD-U with ALS, ALS, and a broadening spectrum of other disorders. It is anticipated that these discoveries and a revised nosology of FTLD will contribute toward an accurate diagnosis, and facilitate the development of new diagnostic tests and therapeutics.

Figure 1

Mutations in the TAR DNA-binding protein 43 (TDP-43) encoded by the TARDBP gene in familial (FALS) and sporadic amyotrophic lateral sclerosis (SALS). Schematic diagram of functional domains and mutations in the coding region are indicated using the amino acid numbering of the 414 amino acid protein. RRM1, RNA recognition motif 1; RRM2, RNA recognition motif 2; NL, nuclear localization signal; NE, nuclear export signal; hnRNP, heterogeneous nuclear ribonucleoprotein interaction domain. TARDBP mutations: autosomal-dominant FALS (black), SALS (green).

Figure 2

TDP-43 proteinopathy in FTLD-U. Adjacent sections of superficial frontal neocortex showing neuronal cytoplasmic inclusions (NCIs), dystrophic neurites (DNs), and isolated neuronal intranuclear inclusions (NIIs), stained for both ubiquitin (a) and TDP-43 (b). NCIs in the dentate granule cells stain for ubiquitin (c) and TDP-43 (d). Neuronal and glial inclusions include: NCI (e), round and lentiform NIIs (f, g); skein-like (h) and compact round (i) NCIs in lower motor neurons; and a glial cytoplasmic inclusion (GCI) (j). (a, c) ubiquitin immunohistochemisty; (b, d, e–j) TDP-43 immunohistochemistry. Bars 10 μm (a–d); 5 μm (e–j). Source: Cairns et al. [60] with permission from the American Society for Investigative Pathology.

Figure 3

FTLD-U subtypes 1–4. (a) Type 1 is characterized by long dystrophic neurites (DNs) in laminae II/III with relatively few neuronal cytoplasmic inclusions (NCIs) and no neuronal intranuclear inclusion (NII). (b) Type 2 has numerous NCIs, relatively few DNs, and no NII. (c) Type 3 has numerous NCIs and DNs and an occasional NII. (d) Type 4 pathology is characterized by numerous NIIs and DNs but few NCIs. TDP-43 immunohistochemistry. Bar 10 μm (a–d). Source: Cairns et al. [60] with permission from the American Society for Investigative Pathology.