Do TDP-43 Aggregation and Tau Aggregation Have Overlapping Mechanisms?

The diverse processes of neurodegeneration are all running at the same time in an aging brain, with some individuals exhibiting more of one or less of another. It is challenging to pick apart distinct mechanisms in aging tissue to decide whether not they contribute to one another, or share specific underlying causes. The question of the direction of causation for specific mechanisms in aging is similarly challenging. Here, researchers discuss possible links and overlapping mechanisms for the aggregation of altered forms of TDP-43 and tau, both characteristic of the aging brain.

Autopsy-based research has revealed that comorbid pathology often has a disease-specific manner, in terms of the biochemical properties, morphological characteristics, and spatial distributions of aggregates, and has an impact for clinical phenotypes. Genetic studies have identified overlapping genetic risk factors between limbic-predominant age-related TDP-43 encephalopathy (LATE) and Alzheimer's disease (AD) or between TDP-associated ALS and frontotemporal dementia or tauopathies. These facts indicate that comorbid pathology is not an incidental bystander, but a part of the disease pathogenesis. It will be important to determine when a TDP-43 or tau pathology is comorbid during disease pathogenesis; antemortem studies using functional neuroimaging targeting aggregated proteins will be useful in the future.

Basic research findings have suggested that the molecular pathways are partially overlapped between TDP-43 proteinopathies and tauopathies. In vivo studies have revealed that aggregated TDP-43 altered the splicing of tau or exacerbated tau aggregation. Moreover, perturbation of the autophagosome-lysosome system-related molecules has been reported in both TDP-43 proteinopathy and tauopathy models. However, it currently seems to be difficult to reproduce the condition of double proteinopathy comprising TDP-43 and tau pathologies by altering just one of the known related molecules or genes. This fact suggests that pathogeneses of TDP-43 proteinopathies and tauopathies arise from multifactorial and polygenetic processes. Further investigations to clarify the pathogenetic factors that are shared by a broad spectrum of neurodegenerative disorders will establish key therapeutic targets.