Abstract
TAR DNA binding protein 43 (TDP-43) is a versatile RNA/DNA binding protein involved in RNA-related metabolism. Hyper-phosphorylated and ubiquitinated TDP-43 deposits act as inclusion bodies in the brain and spinal cord of patients with the motor neuron diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While the majority of ALS cases (90–95%) are sporadic (sALS), among familial ALS cases 5–10% involve the inheritance of mutations in the TARDBP gene and the remaining (90–95%) are due to mutations in other genes such as: C9ORF72, SOD1, FUS, and NEK1 etc. Strikingly however, the majority of sporadic ALS patients (up to 97%) also contain the TDP-43 protein deposited in the neuronal inclusions, which suggests of its pivotal role in the ALS pathology. Thus, unraveling the molecular mechanisms of the TDP-43 pathology seems central to the ALS therapeutics, hence, we comprehensively review the current understanding of the TDP-43's pathology in ALS. We discuss the roles of TDP-43's mutations, its cytoplasmic mis-localization and aberrant post-translational modifications in ALS. Also, we evaluate TDP-43's amyloid-like in vitro aggregation, its physiological vs. pathological oligomerization in vivo, liquid-liquid phase separation (LLPS), and potential prion-like propagation propensity of the TDP-43 inclusions. Finally, we describe the various evolving TDP-43-induced toxicity mechanisms, such as the impairment of endocytosis and mitotoxicity etc. and also discuss the emerging strategies toward TDP-43 disaggregation and ALS therapeutics.
Highlights
TAR DNA binding protein-43 (TDP-43) was identified in 1995 as a repressor protein associated with HIV-1 transcription, which binds to the trans-active response element DNA sequence of the viral genome and is critical for the regulation of the viral gene expression (Ou et al, 1995)
In 2006, TAR DNA binding protein 43 (TDP-43) was identified as a key component of the insoluble and ubiquitinated inclusions in the brains of patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD or FTLD-TDP) diseases (Arai et al, 2006; Neumann et al, 2006)
TDP-43 interacts with NFκB and acts as a co-activator of NFκB in ALS patient’s glial and neuronal cells inducing the production of pro-inflammatory cytokines and neurotoxic mediators
Summary
TAR DNA binding protein-43 (TDP-43) was identified in 1995 as a repressor protein associated with HIV-1 transcription, which binds to the trans-active response element DNA sequence of the viral genome and is critical for the regulation of the viral gene expression (Ou et al, 1995). Numerous mutations in the TARDBP gene have been identified to be associated with ALS and FTLD (Sreedharan et al, 2008; Buratti, 2015) (Figure 2) The effects of these mutations on the TDP-43 protein include: increased propensity to aggregate, enhanced cytoplasmic mislocalization, altered protein stability, resistance to proteases or modified binding interactions with other proteins etc. TIA1 is involved in stress granule (SG) formation and participates in direct physical or RNA-dependent association with TDP-43 in SGs. TIA1 mutations identified in ALS increase its phase separation propensity, disrupt the normal disassembly of SGs and promote the accumulation of non-dynamic SGs containing the TDP-43 protein. TDP-43 interacts with NFκB and acts as a co-activator of NFκB in ALS patient’s glial and neuronal cells inducing the production of pro-inflammatory cytokines and neurotoxic mediators
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