Mechanisms of disease in frontotemporal lobar degeneration: gain of function versus loss of function effects

Abstract

Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Three major proteins are implicated in its pathogenesis. About half of cases are characterized by depositions of the microtubule associated protein, tau (FTLD-tau). In most of the remaining cases, deposits of the transactive response (TAR) DNA-binding protein with Mw of 43 kDa, known as TDP-43 (FTLD-TDP), are seen. Lastly, about 5-10 % of cases are characterized by abnormal accumulations of a third protein, fused in sarcoma (FTLD-FUS). Depending on the protein concerned, the signature accumulations can take the form of inclusion bodies (neuronal cytoplasmic inclusions and neuronal intranuclear inclusions) or dystrophic neurites, in the cerebral cortex, hippocampus and subcortex. In some instances, glial cells are also affected by inclusion body formation. In motor neurone disease (MND), TDP-43 or FUS inclusions can present within motor neurons of the brain stem and spinal cord. This present paper attempts to critically examine the role of such proteins in the pathogenesis of FTLD and MND as to whether they might exert a direct pathogenetic effect (gain of function), or simply act as relatively innocent witnesses to a more fundamental loss of function effect. We conclude that although there is strong evidence for both gain and loss of function effects in respect of each of the proteins concerned, in reality, it is likely that each is a single face of either side of the coin, and that both will play separate, though complementary, roles in driving the damage which ultimately leads to the downfall of neurons and clinical expression of disease.

Fig. 1

The molecular and genetic classification of FTLD. Three distinct neuropathologic categories may be identified based on the molecular pathology of the misfolded protein within the inclusion: FTLD-Tau, FTLD-TDP, and FTLD-FUS; the molecular pathology of a fourth category, FTLD with epitopes of the ubiquitin–proteasome system (FTLD-UPS), remains indeterminate. 3R, 4R, 3R/4R the predominant tau isoform within the inclusion; PICK, Pick’s disease; FTLD with microtubule-associated protein tau (MAPT) mutation with inclusions of 3R, 4R, or 3R and 4R tau protein; CBD, corticobasal degeneration; PSP, progressive supranuclear palsy; AGD, argyrophilic grain disease; TOD, tangle only dementia; WMT-GGI, white matter tauopathy with globular glial inclusions; FTLD-U, FTLD with ubiquitin inclusions, now called FTLD-TDP; FTLD with progranulin (GRN) mutation; FTLD with TAR DNA-binding protein 43 (TARDBP) gene mutation; FTLD with valosin-containing protein (VCP) mutation; FTLD with C9ORF72 expansion, chromosome 9-linked FTLD with C9ORF72 hexanucleotide repeat expansion; NIFID neuronal intermediate filament inclusion disease; aFTLD-U atypical FTLD with ubiquitin inclusions; BIBD basophilic inclusion body disease; FTLD with fused in sarcoma (FUS) mutation; FTLD with charged multivesicular body protein 2B (CHMP2B) mutation. There may still be unclassified entities within each molecular pathology grouping (modified from [12])