TDP-43 proteinopathies: neurodegenerative protein misfolding diseases without amyloidosis.
In this review, we summarize recent advances in understanding frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS) and related neurodegenerative disorders that are collectively known as TDP-43 proteinopathies, since transactive response DNA-binding protein 43 (TDP-43) was recently shown to be the major component of the ubiquitinated inclusions that are their pathological hallmarks. TDP-43 proteinopathies are distinct from most other neurodegenerative disorders because TDP-43 inclusions are not amyloid deposits. Besides TDP-43-positive inclusions, both sporadic and familial forms of FTLD and ALS have the pathologic TDP-43 signature of abnormal hyperphosphorylation, ubiquitination and C-terminal fragments in affected brain and spinal cord, suggesting that they share a common mechanism of pathogenesis. Thus, these findings support the concept that FTLD and ALS represent a clinicopathologic spectrum of one disease, that is, TDP-43 proteinopathy.
Kwong
Linda K
LK
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA.
Uryu
Kunihiro
K
Trojanowski
John Q
JQ
Lee
Virginia M-Y
VM
D000686:Amyloidosis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D017510:Protein Folding; D025801:Ubiquitin
D004268:DNA-Binding Proteins; D025801:Ubiquitin