Molecular Dissection of TDP-43 as a Leading Cause of ALS/FTLD

Abstract

TAR DNA binding protein 43 (TDP-43) is a DNA/RNA binding protein involved in pivotal cellular functions, especially in RNA metabolism. Hyperphosphorylated and ubiquitinated TDP-43-positive neuronal cytoplasmic inclusions are identified in the brain and spinal cord in most cases of amyotrophic lateral sclerosis (ALS) and a substantial proportion of frontotemporal lobar degeneration (FTLD) cases. TDP-43 dysfunctions and cytoplasmic aggregation seem to be the central pathogenicity in ALS and FTLD. Therefore, unraveling both the physiological and pathological mechanisms of TDP-43 may enable the exploration of novel therapeutic strategies. This review highlights the current understanding of TDP-43 biology and pathology, describing the cellular processes involved in the pathogeneses of ALS and FTLD, such as post-translational modifications, RNA metabolism, liquid-liquid phase separation, proteolysis, and the potential prion-like propagation propensity of the TDP-43 inclusions.

Keywords: ALS; FTLD; RNA metabolism; TDP-43; aggregation; neurodegenerative diseases; phase separation.

Figure 1

The structure of TAR DNA-binding protein 43 (TDP-43) protein. TDP-43 is composed of an N-terminal region, two RNA recognition motifs (RRM1 and RRM2), a nuclear localization signal (NLS), a nuclear export signal (NES), and a C-terminal region (with a prion-like glutamine-/asparagine-rich [Q/N] region and a glycine-rich region). The numbers represent amino acid positions.

Figure 2

Molecular mechanisms underlying TDP-43 pathogenesis. Various mechanisms have been identified in the TDP-43 pathogenesis. The impairments of TDP-43 autoregulation and nucleocytoplasmic shuttling result in the dysregulation of RNA metabolism and increased cytoplasmic TDP-43 mislocalization. TDP-43 mislocalization triggers various post-translational modifications, including hyperphosphorylation, ubiquitination, acetylation, and C-terminal fragmentation, which facilitate TDP-43 oligomerization and aggregation. The FALS-linked mutations enhance intrinsic aggregation. The nuclear depletion and cytoplasmic aggregation of TDP-43 induce multiple cytotoxic effects, such as aberrant stress granule dynamics, liquid–liquid phase separation, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, impaired axonal transport, and proteolysis dysfunction. TDP-43 aggregates show prion-like cell-to-cell propagation, which may confer the disease progression.

Figure 3

The distributions of TDP-43 pathology in the extra motor regions. The distribution of TDP-43 pathology in ALS-FTLD differs depending on the clinical types of cognitive impairments, such as: (A) executive dysfunction; (B) language dysfunction; (C) verbal fluency dysfunction; (D) behavioral dysfunction; and (E) semantic aphasia. Furthermore, (F) Limbic-predominant age-related TDP-43 encephalopathy (LATE) exhibits TDP-43 pathology in the limbic system, the frontal lobe, and the temporal lobe. The red areas show the distributions of TDP-43 pathology in the cerebrum.