TDP‐43 pathology in polyglutamine diseases: With reference to amyotrphic lateral sclerosis

A nuclear protein, transactivation response ( TAR ) DNA binding protein 43 kDa ( TDP ‐43), is the major component of neuronal cytoplasmic inclusions ( NCIs ) in frontotemporal lobar degeneration with ubiquitin inclusions ( FTLD ‐ U ) and sporadic amyotrophic lateral sclerosis ( SALS ). While initially thought to be relatively specific to FTLD ‐ U and ALS , TDP ‐43 pathology has now been detected in a number of other neurodegenerative diseases, including A lzheimer's disease and P arkinson's disease. In such tauopathies and α‐synucleinopathies, occurrence of TDP ‐43‐positive neuronal cytoplasmic inclusions may be associated with other distinct molecular pathologic processes primarily involving their own pathological proteins, tau and α–synuclein, respectively (secondary TDP ‐43 proteinopathies). On the other hand, in several polyglutamine ( polyQ ) diseases, TDP ‐43 appears to play an important pathomechanistic role. Interestingly, intermediate‐length polyQ expansions (27–33 Qs ) in ataxin 2, the causative gene of spinocerebellar ataxia type 2, have recently been reported to be a genetic risk factor for SALS . Here, with a review of the literature, we discuss the relationship between ALS and polyQ diseases from the viewpoint of TDP ‐43 neuropathology.