Possible concurrence of TDP‐43, tau and other proteins in amyotrophic lateral sclerosis/frontotemporal lobar degeneration

Transactivation response DNA‐binding protein 43 kDa (TDP‐43) has been regarded as a major component of ubiquitin‐positive/tau‐negative inclusions of motor neurons and the frontotemporal cortices in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Neurofibrillary tangles (NFT), an example of tau‐positive inclusions, are biochemically and morphologically distinguished from TDP‐43‐positive inclusions, and are one of the pathological core features of Alzheimer disease (AD). Although ALS/FTLD and AD are distinct clinical entities, they can coexist in an individual patient. Whether concurrence of ALS/FTLD‐TDP‐43 and AD‐tau is incidental is still controversial, because aging is a common risk factor for ALS/FTLD and AD development. Indeed, it remains unclear whether the pathogenesis of ALS/FTLD is a direct causal link to tau accumulation. Recent studies suggested that AD pathogenesis could cause the accumulation of TDP‐43, while abnormal TDP‐43 accumulation could also lead to abnormal tau expression. Overlapping presence of TDP‐43 and tau, when observed in a brain during autopsy, should attract attention, and should initiate the search for the pathological substrate for this abnormal protein accumulation. In addition to tau, other proteins including α‐synuclein and amyloid β should be also taken into account as candidates for an interaction with TDP‐43. Awareness of a possible comorbidity between TDP‐43, tau and other proteins in patients with ALS/FTLD will be useful for our understanding of the influence of these proteins on the disease development and its clinical manifestation.