TDP-43 proteinopathy

TDP-43 proteinopathies are a set of neurodegenerative disorders characterized pathologically by cytoplasmic inclusions composed of TDP-43. The pathology has been implicated in three major diseases:

• amyotrophic lateral sclerosis (vast majority of cases)
• frontotemporal lobar degeneration (slight majority of cases of FTLD, known as FTLD-TDP)
• limbic-predominant age-related TDP-43 encephalopathy (by definition; often diagnosed clinically as dementia of the Alzheimer type)

Others neurodegenerative disorders are less well known to feature TDP-43 proteinopathy ^1,4,5:

• chronic traumatic encephalopathy
• Huntington disease
• Parkinson disease and variants, including postencephalitic parkinsonism and amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam

Pathology

TDP-43 is the abbreviation for transactive response (TAR) DNA-binding protein of 43 kDa, which is encoded by the TARDBP gene. The protein binds to nucleic acids and some proteins, serving multiple functions in the regulation of gene expression at the transcription and translation levels. It is expressed in nearly all tissues normally. In disease states, the protein is hyperphosphorylated, ubiquitinated, and cleaved to generate C-terminus fragments ^2,4. Cells in affected central nervous system regions stain with antibodies against phosphorylated TDP-43, demonstrating aggregates of protein mislocalized to the cytoplasm ^3,4.