With the advent of new technologies in medicine and related biomedical sciences, concepts of neurodegenerative diseases continue to be refined, and novel disease entities emerge. For example, based on advances over the past 25 years, we now know that nearly all neurodegenerative disease are protein misfolding disorders characterized by pathological central nervous system (CNS) protein aggregates, alterations in the solubility and metabolism of corresponding disease proteins, and mutations in genes that encode major disease proteins of familial disorders and their sporadic counterparts, including the genes encoding tau, amyloid-β, α-synuclein, and others. The phenotypic features of these diseases are highly variable, but correlations between genetic abnormalities, clinical features and underlying neuropathology, as well as mechanisms of neurodegeneration, are recognized. However, we are far from understanding the precise relationships between genotypes and disease phenothypes in common as well as uncommon disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) in addition to frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS). In this review, we summarize recent advances in ALS and FTD that have resulted from development of the concept that these disorders represent a spectrum of manifestations of TDP-43 proteinopathy that are so-named because they are linked to pathological abnormalities in the nuclear protein known as the human immunodeficiency virus type 1 transactive response DNA-binding protein with a Mr of 43 kD (TDP-43) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) which is commonly referred now to as TDP-43.
Historically, amyotrophic lateral sclerosis (ALS) has been considered to be the prototypical pyramidal motor system neurodegenerative disease. The presence of additional features has usually been considered to exclude the diagnosis of classical ALS, and therefore ALS with additional features was referred to as an ALS-Plus syndrome according to El Escorial clinical diagnostic criteria.1,2
In fact, the 1998 El Escorial revised criteria for a diagnosis of ALS include: (i) evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiological or neuropathologic examination; (ii) evidence of upper motor neuron (UMN) degeneration by clinical examination; and (iii) progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination. Further, these criteria included the absence of: (i) electrophysiological and pathological evidence of other disease processes that might explain the signs of LMN and/or UMN degeneration; and (ii) neuroimaging evidence of other disease processes, which might explain the observed clinical and electrophysiological signs.1
In terms of neuropathology, degeneration of the UMN and LMN with motor neuron cytoplasmic inclusions immunoreactive for ubiquitin and corticospinal tract degeneration are considered to be diagnostic for ALS.3
The spectrum of inclusions found in ALS is heterogeneous, morphologically including: (i) filamentous aggregations/threads/skeins; (ii) small granules and Bunina bodies; and (iii) larger frayed, basophilic, and Lewy body-like inclusions. However, besides this diagnostic LMN and UMN degeneration, ubiquitin-inclusion pathology had increasingly been described in a more widespread distribution, such as the ubiquitin-positive neuronal inclusions found in the neocortex or hippocampus, especially in association with dementia (ALS-D).4,5
The concept of ALS goes back to Jean-Martin Charcot (1825–1893), who described this disorder more than 100 years ago, which is the most prevalent neurodegenerative motor neuron disease (MND), while the concept of FTD emerged at about the same time with a report of Arnold Pick (1851–1924), who described cases of a dementia with severe, circumscribed atrophy of frontotemporal regions, now known as Pick’s disease (PiD), which is one of the most widely recognized forms of FTD. Cases with dementia in which argyrophilic intraneuronal inclusions (Pick bodies) and ballooned neurons are seen in the post mortem brain solidified the concept of PiD because these lesions distinguished these patients from those with other types of dementias such asAD, which was first reported by Alois Alzheimer (1864–1915) to be a cognitive disorder associated with neurofibrillary tangles and amyloid plaques. However, it became increasingly clear that many patients with PiD-like clinical features did not show neuropathological evidence of PiD, and a plethora of alternative terms were used for these non-PiD and non-AD dementias.6–8
Not surprisingly, the classification of FTD, which also is referred to as frontotemporal lobar degeneration (FTLD), has been fraught with controversy due in large part to substantial gaps in the understanding of the cellular and molecular neuropathological correlates of the clinical manifestations of FTLDs. As the clinical manifestations of different FTLD variants do not enable prediction of the neuropathological or genetic basis of the dementia in a given patient, it was recommended that the clinically diverse variants of FTLD should be referred to collectively as FTLD to emphasize the shared clinical features enabling differentiation from other dementias during life, but without making assumptions about their neuropathological correlates or underlying disease processes.9
More recent evidence on the convergence of the different clinical syndromes in both FTLDs with tau pathology (i.e., tauopathies which account for ~45% of FTLD cases) or without associated tau pathology during the disease course supports this notion.10,11
Moreover, “ubiquitin only dementia” has been shown to account for ~50% of FTLD cases, and FTLD-U is distinguished from FTLD tauopathies (i.e. FTLD-Tau) by the presence of frontotemporal degeneration and ubiquitin-positive, but tau- and α-synuclein-negative inclusions. The cardinal clinical features of all FTLD variants are non-amnestic cognitive impairments encompassing changes in social behavior often with disinhibition and language difficulties.10
Using ubiquitin and novel monoclonal antibodies generated from FTLD-U brains, at least four morphological subtypes of FTLD-U were identified based on the type and distribution of these ubiquitin-positive inclusions throughout the frontotemporal cortex and hippocampus.12,13
In 2006, the notion that pathological TDP-43 is involved in human disease was proposed when TDP-43 was discovered by Neumann et al.
to be the major disease protein in FTLD-U (now known as FTLD-TDP), FTLD with MND (FTLD-MND) and ALS, suggesting a common pathogenesis linked to TDP-43 abnormalities in these disorders, which was rapidly confirmed by Arai et al
Thus, we recently proposed a classification scheme in which pathological TDP-43 is the major disease defining pathology in so-called primary TDP-43 proteinopathies, which mainly includes ALS, FTLD-TDP and their transition forms, while a second category of disorders includes neurodegenerative diseases wherein there is concomitant TDP-43 pathologies, and a third group comprises those neurodegenerative conditions with minor or no significant TDP-43 pathology.16
This scheme reflects the considerable overlap of clinicopathological features between all neurodegenerative diseases as reviewed elsewhere.17
Recently, detailed clinico-pathological studies on the whole spectrum of TDP-43-related neurodegeneration have become available, and have contributed to establishing the significance of pathological TDP-43 for ALS and FTLD-U.18
Here, we focus this review on the major TDP-43 proteinopathies.