RNA-binding proteins in neurodegenerative disease: TDP-43 and beyond

Abstract

Neurodegenerative diseases are a diverse group of disorders that affect different neuron populations, differ in onset and severity, and can be either inherited or sporadic. One common pathological feature of most of these diseases is the presence of insoluble inclusions in and around neurons, which largely consist of misfolded and aggregated protein. For this reason, neurodegenerative diseases are typically thought to be disorders of aberrant protein processing, in which the cumulative effects of misfolded protein aggregates overwhelm the neuron's proteostatic capacity. However, a growing body of evidence suggests a role for abnormal RNA processing in neurodegenerative disease. The importance of RNA metabolism in disease was highlighted by the discovery of TDP-43 (TAR DNA-binding protein of 43 kDa), an RNA-binding protein (RBP), as a primary component of insoluble aggregates in patients with sporadic amyotrophic lateral sclerosis (ALS). Subsequently, inherited mutations in TDP-43 and the structurally related RBP, FUS/TLS (fused in sarcoma/translated in liposarcoma), were found to cause ALS. These exciting findings have ushered in a new era of ALS research in which the deregulation of RNA metabolism is viewed as a central cause of motor neuron deterioration. In addition, the fact that neuropathologically and anatomically distinct neurodegenerative diseases display altered RNA metabolism suggests that common pathologic mechanisms may underlie many of these disorders.

Figure 1

Comparison of domain architecture in RBPs discussed in this review. Domains in red are known or potential DNA/RNA binding domains. Orange boxes indicate the nuclear localization sequence (NLS); green boxes indicate position of repeats expanded during disease. RRM, RNA recognition motif; ZNF, zinc finger domain; CCD, coiled-coil domain; RNP, ribonucleoprotein-type RNA binding domain; KH, K-homology domain; Lsm, like-Sm domain; LsmAD, Lsm-associated domain; PAM2, PABP-interacting motif 2. Other abbreviations indicate amino acids enriched in indicated domains. Dashes indicate long interdomain regions that have been truncated for clarity.

Figure 1

Comparison of domain architecture in RBPs discussed in this review. Domains in red are known or potential DNA/RNA binding domains. Orange boxes indicate the nuclear localization sequence (NLS); green boxes indicate position of repeats expanded during disease. RRM, RNA recognition motif; ZNF, zinc finger domain; CCD, coiled-coil domain; RNP, ribonucleoprotein-type RNA binding domain; KH, K-homology domain; Lsm, like-Sm domain; LsmAD, Lsm-associated domain; PAM2, PABP-interacting motif 2. Other abbreviations indicate amino acids enriched in indicated domains. Dashes indicate long interdomain regions that have been truncated for clarity.

Figure 2

ALS-associated mutations in TDP-43 and FUS/TLS (adapted from Dormann et al., Ref. 161).

Figure 3

Speculative mechanism of TDP-43 deregulation and toxicity in ALS. (A) Function and proteostatic regulation of TDP-43 in healthy neurons. Under normal conditions TDP-43 is almost exclusively a nuclear protein, where it participates in pre-mRNA splicing and transcriptional repression. Cytosolic TDP-43 may promote mRNA stability and translation, and is degraded by both proteasomal and autophagosomal pathways. (B) Deregulation of TDP-43 in pre-symptomatic, vulnerable neurons. Neuronal stressors including TDP-43 mutation, excitotoxicity, ER stress, and alterations in calcium and ATP homeostasis lead to changes in neurons before the onset of gross neurodegeneration. Shuttling of TDP-43 shifts such that more protein is transported to the cytoplasm. TDP-43 protein levels increase due to both reduced degradation and less autoregulation. Increased TDP-43 protein in the cytoplasm leads to changes in processes normally regulated by TDP-43, such as transcription and splicing. Increased cell stress promotes the incorporation of TDP-43 and other proteins into stress granules. (C) TDP-43 deregulation in ALS. In the degenerating neuron, TDP-43 is exclusively in the cytoplasm, where the degradative capacity of the cell is overwhelmed and insoluble aggregates form. Stress granules may nucleate aggregation. TDP-43 autoregulation is reduced further such that even more protein is produced. Loss of TDP-43 in the nucleus and sequestration in aggregates leads to gene expression changes due to the loss of TDP-43 regulation of transcription and splicing.

Figure 3

Speculative mechanism of TDP-43 deregulation and toxicity in ALS. (A) Function and proteostatic regulation of TDP-43 in healthy neurons. Under normal conditions TDP-43 is almost exclusively a nuclear protein, where it participates in pre-mRNA splicing and transcriptional repression. Cytosolic TDP-43 may promote mRNA stability and translation, and is degraded by both proteasomal and autophagosomal pathways. (B) Deregulation of TDP-43 in pre-symptomatic, vulnerable neurons. Neuronal stressors including TDP-43 mutation, excitotoxicity, ER stress, and alterations in calcium and ATP homeostasis lead to changes in neurons before the onset of gross neurodegeneration. Shuttling of TDP-43 shifts such that more protein is transported to the cytoplasm. TDP-43 protein levels increase due to both reduced degradation and less autoregulation. Increased TDP-43 protein in the cytoplasm leads to changes in processes normally regulated by TDP-43, such as transcription and splicing. Increased cell stress promotes the incorporation of TDP-43 and other proteins into stress granules. (C) TDP-43 deregulation in ALS. In the degenerating neuron, TDP-43 is exclusively in the cytoplasm, where the degradative capacity of the cell is overwhelmed and insoluble aggregates form. Stress granules may nucleate aggregation. TDP-43 autoregulation is reduced further such that even more protein is produced. Loss of TDP-43 in the nucleus and sequestration in aggregates leads to gene expression changes due to the loss of TDP-43 regulation of transcription and splicing.