Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases

Abstract

Ever since the significance of pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) for human disease has been recognized in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U), a number of publications have emerged reporting on this pathology in a variety of neurodegenerative diseases. Given the heterogeneous and, in part, conflicting nature of the recent findings, we here review pathological TDP-43 and its relationship to human disease with a special focus on ALS and FTLD-U. To this end, we propose a classification scheme in which pathological TDP-43 is the major disease defining pathology in one group, or is present in addition to other neurodegenerative hallmark pathologies in a second category. We conclude that the TDP-43 proteinopathies represent a novel class of neurodegenerative disorders akin to alpha-synucleinopathies and tauopathies, with the concept of ALS and FTLD-U to be widened to a broad clinico-pathological multisystem disease, i.e., TDP-43 proteinopathy.

Fig. 1

43 kDa nuclear trans-active response DNA-binding protein (TDP-43) multisystem diseases: clinico-pathological spectrum. Schematic illustration of the concept of a clinico-pathological spectrum of the major TPD-43 diseases extending from frontotemporal degeneration with ubiquitin positive, tau and α-synuclein negative inclusions (FLTD-U) at one end to amyotrophic lateral sclerosis (ALS) at the other. Blue arrowhead-like triangles denote clinical syndrome with motor neuron disease decreasing and dementia increasing from left to right. Color change from yellow to red in central box denotes increasing spread and severity of TDP-43 pathology in the brain and spinal cord, as an approximate estimation. Specifically, yellow represents predominant involvement of the spinal cord and red represents predominant involvement of cortical areas. Other brain areas are not as explicitly represented in this color coded diagram. MND motor neuron disease, ALS-D ALS with dementia, FTLD-MND frontotemporal degeneration with MND