TDP-43 Proteinopathies

The grounding supports TDP-43 mislocalization and aggregation as a central disease-associated process, and notes that mutations in TDP-43 are causative in familial ALS. It also indicates that TDP-43 pathology occurs in sporadic ALS and in limbic-predominant age-related TDP-43 encephalopathy. Beyond this, no specific external causes are supported.

The disease is characterized by abnormal metabolism and pathological processing of TDP-43, including phosphorylation, ubiquitination, cleavage, and aggregation into cytoplasmic inclusions. In ALS, these aggregates are described as driving pathology through both gain- and loss-of-function mechanisms, including sequestration of normal TDP-43 function and disruption of cellular processes. The literature also links TDP-43 pathology to abnormal phase transitions and liquid-liquid phase separation.

Older age is supported as a risk factor for limbic-predominant age-related TDP-43 encephalopathy, which generally affects older subjects. The grounding also supports the presence of comorbid brain pathologies in many cases of LATE, but does not establish these as risk factors. No other risk factors are supported.