TDP-43: a novel neurodegenerative proteinopathy

Abstract

Over the past decade, it has become clear that there is a significant overlap in the clinical spectrum of frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS). The identification of TDP-43 as the major disease protein in the pathology of both frontotemporal lobar degeneration with ubiquitin inclusions and ALS provides the first molecular link for these diseases. Pathological TDP-43 is abnormally phosphorylated, ubiquitinated, and cleaved to generate carboxy-terminal fragments in affected brain regions. The normal nuclear expression of TDP-43 is also reduced leading to the hypothesis that sequestration of TDP-43 in pathological inclusions contributes to disease pathogenesis. Thus, TDP-43 is the newest member of the growing list of neurodegenerative proteinopathies, but unique in that it lacks features of brain amyloidosis.

Figure 1. Proposed classification scheme for TDP-43 proteinopathies

Despite the significant clinical, genetic, and neuropathologic heterogeneity within FTLD and ALS, TDP-43 is a common pathological substrate linking FTLD-U and ALS caused by different genetic alterations. This observation supports the hypothesis that FTLD and ALS represent two extremes of a clinicopathological spectrum of one disease, TDP-43 proteinopathies. FTLD-U is subclassified based on distinct morphological, genetic, and clinical parameters while dementia is reported in a significant subset of ALS patients. ALS, amyotrophic lateral sclerosis; DN, dystrophic neurites; fALS, familial amyotrophic lateral sclerosis; FTLD, frontotemporal lobar degeneration; FTLD-U, frontotemporal lobar degeneration with ubiquitin inclusions; GCI, glial cytoplasmic inclusions; NCI, neuronal cytoplasmic inclusions; NII, neuronal intranuclear inclusions; MND, motor neuron disease; PGRN, progranulin; SOD1, Cu/Zn superoxide dismutase; VCP, valosin-containing protein.

Figure 2. Model of TDP-43 disease pathogenesis

The aggregation of TDP-43 (depicted in red) in neurons as well as glia leads to its sequestration in cytoplasmic and intranuclear inclusions as well as dystrophic neurites. The sequestration of TDP-43 may be toxic due to loss of normal function. Alternatively, the aggregation of TDP-43, in particular the C-terminal fragment(s) may lead to a toxic gain of function.