RNA Splicing in Neurodegeneration

RNA Splicing in Neurodegeneration

Overview

RNA splicing is a fundamental post-transcriptional process that removes introns from precursor messenger RNA (pre-mRNA) and joins exons to produce mature mRNA transcripts. This process is mediated by the spliceosome, a large ribonucleoprotein complex. Emerging evidence demonstrates that dysregulated RNA splicing plays a critical role in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD)[@cooper2014][@belzil2018].

RNA Splicing in Neurodegeneration

Overview

RNA splicing is a fundamental post-transcriptional process that removes introns from precursor messenger RNA (pre-mRNA) and joins exons to produce mature mRNA transcripts. This process is mediated by the spliceosome, a large ribonucleoprotein complex. Emerging evidence demonstrates that dysregulated RNA splicing plays a critical role in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD)[@cooper2014][@belzil2018].

Alternative splicing, wherein a single gene can generate multiple mRNA isoforms, is particularly important for neuronal function. The nervous system has the highest rate of alternative splicing in the human body, and disruption of this process contributes to neurodegeneration through multiple mechanisms including altered protein isoform expression, toxic gain-of-function from aberrant splicing products, and loss of essential neuronal splice variants["@raj2015"].

The Spliceosome and Core Splicing Machinery

Major and Minor Spliceosome

The human spliceosome consists of two distinct complexes:

Major spliceosome (U2-dependent): Processes ~99.5% of pre-mRNA introns. Core components include:

• U1 snRNP: Recognizes the 5' splice site
• U2 snRNP: Binds the branch point adenosine
• U4/U5/U6 tri-snRNP: Catalyzes the splicing reaction

Splicing Factor Families

Key splicing regulators include:

• Serine/arginine-rich (SR) proteins: Phosphorylation-regulated splicing activators
• Heterogeneous nuclear ribonucleoproteins (hnRNPs): Generally function as splicing repressors
• SRRM4: Neural-specific splicing regulator essential for neuronal differentiation
• RBFOX1/2/3: RNA binding fox-1 homolog family, critical for neuron-specific splicing

Dysregulated Splicing in Alzheimer's Disease

Tau Exon 10 Splicing

[Tau protein](/proteins/tau), encoded by the MAPT gene, is central to AD pathogenesis. Alternative splicing of MAPT exon 10 produces isoforms with 3 repeats (3R) or 4 repeats (4R) of the microtubule-binding domain. The 3R:4R ratio is tightly regulated in normal brain (1:1), and dysregulation toward 4R-tau predominance is a hallmark of several tauopathies including progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS)[@qian2014].

Splicing factors regulating tau exon 10:

• SRp20 (SRSF3): Promotes exon 10 inclusion
• SC35 (SRSF2): Promotes exon 10 skipping
• hnRNPs A1/A2: Generally promote exon 10 skipping
• PTBP2: Can shift splicing toward 3R-tau

APP and BACE1 Splicing

Alternative splicing of [APP](/entities/app-protein) (amyloid precursor protein) generates isoforms with varying [amyloid-beta](/proteins/amyloid-beta) (Aβ) production potential. The APP-770 isoform contains the Kunitz protease inhibitor (KPI) domain, which enhances Aβ production. Increased KPI-containing APP isoforms have been observed in AD brain[@belyaev2010].

[BACE1](/entities/bace1) (β-secretase) alternative splicing also influences amyloidogenesis. A BACE1 isoform lacking the prodomain shows altered subcellular localization and may contribute to pathogenic Aβ production in AD.

Dysregulated Splicing in Parkinson's Disease

Alpha-Synuclein Exon Splicing

SNCA (alpha-synuclein) gene undergoes complex alternative splicing producing multiple isoforms (SNCA-126, SNCA-140, and smaller isoforms). Exon 3 inclusion/exclusion produces isoforms with or without the NAC (non-Aβ component) region implicated in aggregation. Altered SNCA splicing patterns have been reported in PD brain, with some studies showing increased inclusion of exon 5 in PD[@beyer2009].

LRRK2 Splicing

LRRK2 (leucine-rich repeat kinase 2) mutations are a common cause of familial PD. Alternative splicing of LRRK2 produces multiple isoforms with differential kinase activity. Studies have identified PD-associated splicing variants that affect LRRK2 subcellular localization and pathogenic signaling.

Parkin and PINK1 Splicing

PRKN (parkin) and PINK1 (PTEN-induced kinase 1) are critical genes in mitochondrial quality control. Alternative splicing of these genes produces isoforms with different functional properties. Splicing variants in both genes have been associated with earlier onset of PD[@sironi2012].

ALS and FTD: Spliceopathies

TDP-43 Pathology

ALS and FTD share a common pathological feature: cytoplasmic aggregates of [TDP-43](/mechanisms/tdp-43-proteinopathy) (TAR DNA-binding protein 43, encoded by TARDBP). Normally a nuclear protein, TDP-43 regulates RNA splicing of numerous neuronal transcripts. In ALS/FTD, TDP-43 mislocalization to the cytoplasm leads to:

• Loss of nuclear splicing function
• Toxic gain-of-function in the cytoplasm
• widespread splicing dysregulation[@lee2012]

C9orf72 Hexanucleotide Repeat Expansion

The most common genetic cause of familial ALS and FTD is a GGGGCC hexanucleotide repeat expansion in the [C9orf72](/entities/c9orf72) gene. This expansion causes disease through three mechanisms:

These mechanisms lead to widespread splicing dysregulation, including altered splicing of UNC13A, a critical determinant of ALS prognosis[@liu2020].

FUS and TDP-43 Interplay

FUS (fused in sarcoma) is another RNA-binding protein mutated in familial ALS. FUS and TDP-43 cooperate in splicing regulation, and disease-causing mutations in either protein disrupt this partnership, leading to coordinated splicing abnormalities.

Therapeutic Implications

Antisense Oligonucleptide Approaches

Antisense oligonucleotides (ASOs) can directly correct pathological splicing:

• ASOs targeting tau exon 10: Shift 3R:4R ratio in PSP models
• ASOs targeting C9orf72: Reduce toxic RNA foci and dipeptide repeats
• ASOs targeting MALAT1: Modulate splicing of disease-relevant genes

Small Molecule Splicing Modulators

Several drug classes can modulate splicing:

• Splice-switching oligonucleotides (SSOs): Steric block of splice sites
• Pseudouridine analogs: Modify spliceosome function
• Natural products: Certain flavonoids modulate SR protein phosphorylation

Gene Therapy Approaches

Viral delivery of wild-type splicing factors:

• AAV-TDP-43: Restore nuclear TDP-43 function in ALS
• AAV-SRRM4: Correct neuronal splicing deficits

Key Splicing Factors in Neurodegeneration

| Factor | Gene | Function | Disease Association |
|--------|------|----------|-------------------|
| TDP-43 | TARDBP | RNA binding, splicing regulation | ALS, FTD |
| FUS | FUS | RNA binding, splicing regulation | ALS |
| TAF15 | TAF15 | RNA binding, transcription/splicing | ALS |
| hnRNPA1 | HNRNPA1 | Splicing repression | ALS, Inclusion body myopathy |
| hnRNPA2B1 | HNRNPA2B1 | Splicing regulation | ALS, CBD |
| SRRM4 | SRRM4 | Neural-specific splicing | ALS, PD |
| RBFOX1 | RBFOX1 | Neuronal splicing regulation | Epilepsy, ASD |

Research Directions

Biomarker Potential

Splicing signatures in cerebrospinal fluid (CSF) and blood represent promising biomarkers:

• SNCA splice variants: PD diagnostic potential
• TARDBP splicing: ALS disease progression marker
• MAPT 3R/4R ratio: Tauopathy classification

iPSC Models

Patient-derived induced pluripotent stem cells (iPSCs) enable study of neuronal splicing:

• Cortical [neurons](/entities/neurons) from ALS/FTD patients show splicing dysregulation
• Correction of splicing defects in isogenic lines
• Drug screening for splicing modulators

See Also

• [Tau Pathology](/mechanisms/tau-pathology)
• [Alpha-Synuclein Pathology](/mechanisms/alpha-synuclein-pathology)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [MAPT Gene](/genes/mapt)
• [SNCA Gene](/genes/snca)
• [TARDBP Gene](/genes/tardbp)

Recent Research Updates (2024-2026)

Recent advances have clarified RNA splicing defects in neurodegeneration:

• C9orf72 repeat expansion and splicing: Studies reveal that GGGGCC repeats in C9orf72 cause aberrant splicing of multiple genes through toxic dipeptide repeat proteins, with antisense oligonucleotides showing promise in clinical trials[@zhang2025].
• Spliceosome dysfunction in ALS/FTD: Research demonstrates that mutations in splicing factors (TDP-43, FUS, U2AF2) disrupt spliceosome assembly and cause widespread splicing changes in ALS and frontotemporal dementia[@lagiertourenne2024].
• Alternative splicing of tau: Recent work identifies specific tau splice variants (3R vs 4R tau) regulated by splicing factors, with implications for Alzheimer's disease and other tauopathies[@himmrich2025].
• RNA-binding protein aggregates: Studies show that TDP-43 and FUS form stress granules and liquid-liquid phase separations that sequester mRNA splicing factors, disrupting neural function[@ramaswami2024].
• Therapeutic splice-modulating oligonucleotides: Antisense oligonucleotides targeting specific splice events (e.g., SOD1, C9orf72) have advanced to clinical trials for ALS[@miller2025].

References

Related Hypotheses

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

• [Serine/Arginine-Rich Protein Kinase Modulation](/hypothesis/h-dca3e907) — <span style="color:#ffd54f;font-weight:600">0.57</span> · Target: SRPK1