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The importance of RNA splicing in neurodegenerative diseases

In Alzheimer's disease, the MAPT gene on chromosome 17 plays an important role because it codes for the microtubule-associated protein tau, which is present in patients in phosphorylated and fibrillar (aggregated) form (tangles) and is typical for the disease (in contrast to beta-amyloid). As described in my book on neurodegeneration in chapter 2.3.4, the mRNA coding for a protein is usually composed of several exons (see figure above). Different exon combinations in the MAPT gene result in a total of six different tau versions (isoforms). They arise from mRNA precursors that are subjected to so-called alternative splicing (RNA splicing). This is a process that refers to the selective excision of non-coding DNA sequences, the so-called introns. Some tau mRNAs also have exon repeats, e.g., of exon 10 (thus, the 3R form of tau contains three exon 10 repeats). In particular, tau molecules aggregate over such tandem repeats and assemble into fibrils.

RNA splicing is determined by splicing factors. Such proteins are often increased in neurons that are first affected by degeneration. For example, the splicing factor PTBP1 is particularly found in neurons that produce pathological tau isoforms and die prematurely. Polypyrimidine tract-binding protein 1 (PTBP1) represents an RNA-binding protein that regulates splicing, thereby affecting axon formation, synaptogenesis, and neuronal apoptosis. Highly specialized neuronal functions thus depend heavily on correctly spliced RNA, and defective regulation of splicing can lead to various neurodegenerative diseases.

Advances in RNA sequencing in recent years have led to the discovery of genetic alterations localized precisely at those sites where splicing factors attach to pre-mRNA. Such aberrations are found, for example, in STMN2 RNA, which encodes the protein stathmin-2. Stathmin-2 is critically involved in the regulation of the cytoskeleton and thus in neuronal plasticity. It therefore plays an important role in the formation of axonal branches, which are essential for regenerative processes. Stathmin-2 is also referred to as SCG10 because it is highly expressed in sympathetic ganglion cells.

Expression of the STMN2 gene is increased by a nucleic acid-binding protein, TAR DNA-binding protein of 43 kDa (TDP-43), in the nucleus. TDP-43 is particularly relevant for transcription and RNA splicing, but also for RNA transport. It is increasingly found outside the nucleus in aging and tends to aggregate in the cytoplasm. Aggregation is enhanced by mutations in the TDP-43 gene, which is therefore associated with diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal degeneration (FTLD) and, more recently, Alzheimer's disease. In this context, almost all ALS patients and up to half of FTLD and Alzheimer's patients are affected by defective TDP-43 regulation.

Accordingly, the term TDP-43 proteinopathy refers to neurodegenerative diseases that exhibit aggregation of the DNA- and RNA-binding protein TDP-43. Loss of TDP-43 in the nucleus leads to quantitative changes in hundreds of RNA transcripts, many of which are incorrectly spliced. This can lead, for example, to a premature stop codon, so that the corresponding proteins are not produced in full length and are therefore inactive. If TDP-43 is missing from the nucleus of motor neurons, for example, functional stathmin-2 will no longer be expressed in sufficient quantities and thus will not be effective in axonal regeneration, microtubule stability and lysosome transport.

The authors of a new study published this year in Science have now identified the TDP-43 binding site on the pre-mRNA of STMN2 in mice in intron 1 of the stathmin gene. Knockout (deletion) of a defined base sequence at this site resulted in defective exon splicing, demonstrating that TDP-43 binding is essential for STMN2 mRNA precursor processing and thus for the production of functional stathmin-2.

The precise characterization of the molecular interaction of STMN2 pre-mRNA and TDP-43 by Michael Baughn and colleagues now makes it possible to target this defective exon splicing, also known as cryptic, with antisense oligonucleotides (ASOs). This is a promising approach to modulating gene expression, as short single-stranded DNA molecules can selectively bind (hybridize) RNA transcripts and are already approved for clinical use in spinal muscular atrophy or Duchenne muscular dystrophy.

Don Cleveland's research group is currently developing a variety of ASOs that target the cryptic exon of STMN2 and can thus take over the blocking function of TDP-43. These oligonucleotides restore expression of functional stathmin-2 in motor neurons deficient in TDP-43. In animal models, axon regeneration and stathmin-2-dependent lysosome transport also improved. Thus, injection of specific ASOs into the neural fluid may represent a therapeutic approach to restore sufficient levels of stathmin-2 in neurons with defective regulation of the STMN2 mRNA precursor. This would be similar to the approach used in the therapy of spinal muscular atrophy (SMA) by correcting the defective splicing of the pre-mRNA of SMN2.


Baughn MW, Melamed Ze, López-Erauskin J, ..., Lagier-Tourenne C, Cleveland DW (2023) Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies. Science 379:1140

O'Brien N, Mizielinska S. (2023) A cryptic clue to neurodegeneration? Science 379:1090

Image credit: iStock/Trinset


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