TDP-43: A new player on the AD field?

Abstract

Alzheimer’s disease accounts for an estimated 60–80% of dementia cases, and is the 5th leading cause of death for people aged 65 and older (Heron, 2008). The cognitive decline and amnestic dementia characteristic of the disease result from brain region-specific neuronal dysfunction and death, leading to memory loss, confusion, and changes in behavior, mood and personality. Ultimately, AD patients require help with daily tasks such as eating, bathing and communicating, primarily from unpaid caregivers including family members and friends. In 2009, the contribution of these unpaid caregivers to our nation was valued at $144 billion. As a result of longer life expectancies and the aging baby boomer population, it is expected that by 2050 the number of people aged 65 and older with AD will be between 11–16 million (Hebert, et al., 2003). It is thus imperative that clinical trials toward potential therapeutic targets, which take many years and millions of dollars to reach completion, are initiated now. The regulation of gene expression in the presence and absence of cellular stress is increasingly recognized to be dependent on post-transcriptional mRNA regulation (Liu-Yesucevitz, et al., 2011). In the absence of stress, mature mRNA is transported from the nucleus to the cytosol where it is translated into protein. However, under stress conditions mRNA may be reversibly bound by RNA binding proteins (RBPs) and converted to quiescent cytoplasmic RNA/protein complexes called stress granules (SGs). TAR DNA-binding protein 43 (TDP-43) is a nuclear protein expressed ubiquitously from the Tardbp gene on chromosome 1 (Liu-Yesucevitz, et al., 2010). It contains two highly conserved DNA/RNA recognition motifs, followed by a C-terminal glycine-rich domain and nuclear localization and export signals, which allow TDP-43 to be continuously shuttled between the nucleus and the cytoplasm. Under normal conditions, the predominant function for TDP-43 identified to date is regulation of nuclear transcription, splicing and stability of RNA transcripts (Kumar-Singh, 2011). However, during stress TDP-43 is sequestered in the cytoplasm as a component of insoluble protein aggregates. TDP-43 may also become cleaved by activated caspases, and the phosphorylated C-terminus has become a hallmark of TDP-43 proteinopathy (Liu-Yesucevitz, et al., 2010, Toh, et al., 2011). Although initially recognized for its role in repressing the human immunodeficiency viruse type 1 (HIV-1) gene (Ou, et al., 1995), recent advances in molecular genetics have identified over 30 mutations in TDP-43 that are linked to amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar dementia (FTLD) (Lagier-Tourenne and Cleveland, 2009), suggesting a causative role for the protein in disease development. Indeed, TDP-43 inclusions occur primarily in degenerating motor neurons of the brain and spinal cord. Thus, RBPs have emerged as an important player in neurodegenerative processes, and are a potential targets for therapeutic development.