Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD-ALS spectrum disorders

Abstract

Aggregation of misfolded TAR DNA-binding protein 43 (TDP-43) is a striking hallmark of neurodegenerative processes that are observed in several neurological disorders, and in particular in most patients diagnosed with frontotemporal lobar degeneration (FTLD) or amyotrophic lateral sclerosis (ALS). A direct causal link with TDP-43 brain proteinopathy was provided by the identification of pathogenic mutations in TARDBP, the gene encoding TDP-43, in ALS families. However, TDP-43 proteinopathy has also been observed in carriers of mutations in several other genes associated with both ALS and FTLD demonstrating a key role for TDP-43 in neurodegeneration. To date, and despite substantial research into the biology of TDP-43, its functioning in normal brain and in neurodegeneration processes remains largely elusive. Nonetheless, breakthroughs using cellular and animal models have provided valuable insights into ALS and FTLD pathogenesis. Accumulating evidence has redirected the research focus towards a major role for impaired RNA metabolism and protein homeostasis. At the same time, the concept that toxic TDP-43 protein aggregates promote neurodegeneration is losing its credibility. This review aims at highlighting and discussing the current knowledge on TDP-43 driven pathomechanisms leading to neurodegeneration as observed in TDP-43 proteinopathies. Based on the complexity of the associated neurological diseases, a clear understanding of the essential pathological modifications will be crucial for further therapeutic interventions.

Figure 1.

Schematic representation of TDP-43 with its protein domain structures and localization of disease-associated mutations. TDP-43 comprises an NLS and NES, respectively, 2 RNA-recognition motifs (RRM1 and RRM2) and a C-terminal glycine-rich region (GRR). Numerous mutations in TARDBP have been identified in sporadic and familial ALS patients and rarely in FTLD patients. Mutations are predicted to enhance aggregation. Furthermore, experimental evidence also suggested that different domain structures of TDP-43 are involved in the aggregation process. Abbreviations: del, deletion; ins, insertion; FL-TDP, full-length TDP-43; GRR, glycine-rich region; UTR, untranslated region.

Figure 2.

Overview of putative mechanisms involved in TDP-43 proteinopathy observed in ALS and FTLD patients. Physiological TDP-43 shuttles between the nucleus and the cytoplasm to exert its cellular functions ranging from gene expression regulation at the transcription and splicing level to mRNA transport and stabilization. Upon cellular stress, TDP-43 is reversibly directed to the cytoplasm and accumulates in SGs. Mutations in several genes (Table 1) have been observed in ALS and FTLD patients with TDP-43 proteinopathy, demonstrating that TDP-43 has a key role in the neurodegeneration process. TDP-43 proteinopathy is characterized by pathological modifications including aggregation, C-terminal cleavage into CTFs, hyperphosphorylation and ubiquitination of TDP-43. Furthermore, extensive research on TDP-43-related pathomechanisms suggests that different putative mechanisms might contribute to TDP-43 aggregation, including impaired protein degradation, alterations of TDP-43-associated splicing events, nuclear transport defects, loss of TDP-43 autoregulation and enhanced self-interaction of TDP-43. Abbreviations: α/β, importin α/β; Ub, ubiquitin; P, phosphorylation; Star *, mutant protein.