Posttranslational modifications of TDP-43

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder that is characterized by the degeneration of upper and lower motor neurons resulting in muscle weakness and paralysis. Frontotemporal dementia (FTD) is the second most common form of dementia after Alzheimer's in individuals under the age of 65, and is characterized by shrinkage within the frontal and temporal lobes of the brain, inducing behavioral changes and language dysfunction. Although ALS and FTD have different phenotypes and affect different parts of the central nervous system, there is strong clinical association between the disorders, with a subset of cases showing both cognitive and motor deficits. Frontotemporal lobar degeneration with TAR DNA-binding protein of 43 kDa (TDP-43)-positive inclusions is a major pathological subtype of FTD that shares a similar molecular phenotype with the majority of ALS cases, whereby the nuclear RNA-binding protein TDP-43 accumulates in large cytoplasmic aggregates in affected neurons. It is hypothesized that aberrant TDP-43 aggregation may cause disease through a toxic loss of function, affecting the regulation of mRNAs implicated in neuronal function, or through a toxic gain of function whereby the presence of the aggregates themselves induces apoptotic signaling pathways. Aberrant TDP-43 aggregates are associated with specific posttranslational modifications (PTMs), the three dominant ones being ubiquitination, phosphorylation, and C-terminal fragmentation. Recent studies have implicated oxidative stress–induced cysteine oxidation and lysine acetylation in impairing TDP-43's capacity to bind its target mRNAs. This chapter will review the literature pertaining to these PTMs, discussing both toxic loss-of-function and gain-of-function mechanisms.