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Review
. 2022 Jul;19(4):1061-1084.
doi: 10.1007/s13311-022-01260-5. Epub 2022 Jul 5.

Emerging Therapies and Novel Targets for TDP-43 Proteinopathy in ALS/FTD

Lindsey R Hayes  1 , Petr Kalab  2
Affiliations
Review

Emerging Therapies and Novel Targets for TDP-43 Proteinopathy in ALS/FTD

Lindsey R Hayes et al. Neurotherapeutics. 2022 Jul.

Abstract

Nuclear clearance and cytoplasmic mislocalization of the essential RNA binding protein, TDP-43, is a pathologic hallmark of amyotrophic lateral sclerosis, frontotemporal dementia, and related neurodegenerative disorders collectively termed "TDP-43 proteinopathies." TDP-43 mislocalization causes neurodegeneration through both loss and gain of function mechanisms. Loss of TDP-43 nuclear RNA processing function destabilizes the transcriptome by multiple mechanisms including disruption of pre-mRNA splicing, the failure of repression of cryptic exons, and retrotransposon activation. The accumulation of cytoplasmic TDP-43, which is prone to aberrant liquid-liquid phase separation and aggregation, traps TDP-43 in the cytoplasm and disrupts a host of downstream processes including the trafficking of RNA granules, local translation within axons, and mitochondrial function. In this review, we will discuss the TDP-43 therapy development pipeline, beginning with therapies in current and upcoming clinical trials, which are primarily focused on accelerating the clearance of TDP-43 aggregates. Then, we will look ahead to emerging strategies from preclinical studies, first from high-throughput genetic and pharmacologic screens, and finally from mechanistic studies focused on the upstream cause(s) of TDP-43 disruption in ALS/FTD. These include modulation of stress granule dynamics, TDP-43 nucleocytoplasmic shuttling, RNA metabolism, and correction of aberrant splicing events.

Keywords: Amyotrophic lateral sclerosis; Autophagy; Frontotemporal dementia; RNA; Stress granules; TDP-43.

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Figures

Fig. 1
Fig. 1
Overview of TDP-43 nuclear/cytoplasmic localization and its links to cytoplasmic aggregation and nuclear loss of function in pre-mRNA splicing. In the nucleus, TDP-43 accumulates at GU-rich sequences primarily within the distal introns of thousands of genes, where it acts to modulate splicing. The loss of nuclear TDP-43, triggered by nuclear clearance or disease-causing mutations, unmasks cryptic splice sites that permit the aberrant inclusion of cryptic exons within mRNA. For example, the aberrant inclusion of the STMN2 cryptic exon 2a generates a premature poly-adenylation start site, resulting in the synthesis of non-functional truncated stathmin-2 protein and loss of its crucial function in axonal regeneration. The predominantly nuclear localization of TDP-43 at steady state results from its active nuclear import via importin α and importin β and export via passive diffusion through nuclear pore complexes. In disease, accumulating cytoplasmic TDP-43 forms progressively insoluble aggregates, through a pathway that can proceed by both SG-dependent and -independent pathways. Both TDP-43 aggregates and SGs sequester importins and nucleoporins, which may hamper TDP-43 nuclear re-import. Clearance of cytoplasmic TDP-43 aggregates is mediated by multiple pathways, including via chaperones, autophagy, the ubiquitin–proteasome system (UPS), and endocytosis. For references, see text
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