RNA Splicing Defects in Neurodegeneration describes a key molecular or cellular mechanism implicated in neurodegenerative disease. This page provides a detailed overview of the pathway components, signaling cascades, and their relevance to conditions such as Alzheimer's disease, Parkinson's disease, and related disorders.
RNA Splicing Defects in Neurodegeneration describes a key molecular or cellular mechanism implicated in neurodegenerative disease. This page provides a detailed overview of the pathway components, signaling cascades, and their relevance to conditions such as Alzheimer's disease, Parkinson's disease, and related disorders.
RNA splicing is a fundamental cellular process by which introns are removed from pre-messenger RNA (pre-mRNA) to generate mature mRNA transcripts. This process is catalyzed by the spliceosome, a large ribonucleoprotein complex composed of five small nuclear ribonucleoproteins (snRNPs) and numerous associated proteins. In neurodegenerative diseases, defects in RNA splicing have emerged as a critical pathogenic mechanism, contributing to protein dysregulation, neuronal dysfunction, and cell death["@liu2024"].
The spliceosome undergoes dynamic assembly and disassembly throughout the splicing cycle. The major (U2-dependent) spliceosome recognizes conserved sequence elements at the 5' splice site, branch point, and 3' splice site to catalyze intron removal with remarkable precision.
Small Nuclear Ribonucleoproteins (snRNPs):
Constitutive splicing removes all introns from pre-mRNA to generate standard mRNA transcripts. Alternative splicing produces multiple mRNA variants from a single gene by selectively including or excluding specific exons or introns, greatly expanding proteomic diversity.
In Alzheimer's disease (AD), RNA splicing defects contribute to disease pathogenesis through multiple mechanisms[@mills2024]:
Tau splicing alterations: The MAPT gene encoding tau protein undergoes aberrant alternative splicing in AD. Inclusion of exon 10 produces 3R (three repeat) tau isoforms, while exclusion produces 4R tau. An imbalance in 3R/4R ratio disrupts microtubule stability and promotes tau aggregation.
APP splicing dysregulation: Alternative splicing of APP (amyloid precursor protein) generates different isoforms with distinct amyloidogenic properties. Increased inclusion of exon 7 and exon 8 produces APP isoforms that may contribute to amyloid-beta generation.
Spliceosome component downregulation: Key spliceosomal proteins including SNRNP70, SNRNP116, and SF3B1 show reduced expression in AD brains, leading to widespread splicing abnormalities.
Intron retention: Recent studies reveal widespread intron retention in AD brains, affecting genes involved in synaptic function, mitochondrial metabolism, and stress responses.
RNA splicing defects in Parkinson's disease (PD) primarily affect genes involved in dopaminergic neuron survival and protein quality control[@bnfer2024]:
LRRK2 splicing: Mutations in LRRK2 (Leucine-Rich Repeat Kinase 2) are a common genetic cause of familial PD. Alternative splicing of LRRK2 produces variants with altered kinase activity and subcellular localization.
SNCA splicing: The gene encoding alpha-synuclein (SNCA) undergoes alternative splicing producing isoforms with different aggregation propensities. Increased inclusion of exon 3 (SNCA-126) or exon 5 (SNCA-140) may influence oligomerization and toxicity.
PARK2/PARKIN splicing: Mutations affecting splicing of the PARKIN gene lead to loss of functional protein and impaired mitophagy.
Splicing factor dysregulation: Splicing factors including HNRNPA2/B1, HNRNPA1, and SRSF2 show altered expression and localization in PD brains.
RNA splicing defects are particularly prominent in ALS, where they affect genes critical for motor neuron survival[@ferrari2024]:
TDP-43 pathology: TDP-43 (TAR DNA-binding protein 43) is an RNA-binding protein that regulates splicing of numerous target genes. In ALS, TDP-43 mislocalizes to cytoplasmic aggregates, leading to loss of its nuclear splicing function.
FUS splicing alterations: FUS (Fused in Sarcoma) is another RNA-binding protein mutated in familial ALS. FUS regulates splicing of genes involved in neuronal development and stress responses.
C9orf72 hexanucleotide repeat: The most common genetic cause of familial ALS involves a GGGGCC hexanucleotide repeat expansion in C9orf72. This repeat produces toxic RNAs that sequester splicing factors, leading to widespread splicing dysregulation.
NEFH splicing: Abnormal splicing of the neurofilament heavy chain (NEFH) gene produces a truncated protein that may contribute to axonal transport deficits.
Frontotemporal dementia (FTD) shares considerable overlap with ALS in terms of RNA splicing defects[@zhang2024]:
TDP-43 inclusion bodies: Like ALS, FTD-TDP shows TDP-43 pathology with consequent splicing abnormalities.
GRN splicing: Progranulin (GRN) gene mutations causing FTD affect splicing efficiency, with some mutations creating cryptic splice sites.
MAPT splicing: Certain MAPT mutations causing FTD alter exon 10 splicing, disrupting the 3R/4R tau ratio.
RNA splicing defects in Huntington's disease (HD) affect genes involved in neuronal function and survival[@hodges2024]:
HTT splicing: The huntingtin gene (HTT) undergoes alternative splicing producing isoforms with different functional properties.
Splicing factor sequestration: Mutant huntingtin protein sequesters splicing factors including SF1 and U2AF, disrupting normal splicing patterns.
Exon skipping: Aberrant exon skipping events have been documented in HD brains, particularly affecting genes involved in synaptic function.
Many neurodegenerative diseases involve aggregation of RNA-binding proteins in the cytoplasm, depleting their nuclear function[@lee2024]:
TDP-43 normally resides in the nucleus where it regulates splicing. In ALS/FTD, it mislocalizes to cytoplasmic inclusions, losing its nuclear function.
FUS similarly aggregates in the cytoplasm in some forms of familial ALS, disrupting its splicing regulatory activity.
hnRNPs including hnRNPA1, hnRNPA2/B1, and hnRNP C show altered localization and function in various neurodegenerative conditions.
Hexanucleotide repeat expansions in genes like C9orf72 undergo repeat-associated non-ATG (RAN) translation, producing toxic dipeptide repeat proteins that may disrupt splicing[@zu2023]:
Dipeptide repeat proteins can sequester splicing factors RNA foci formed by expanded repeats can sequester essential splicing proteins nucleocytoplasmic transport defects may affect splicing factor localization
Splicing is coupled to transcription and chromatin structure:
RNA polymerase II elongation rate influences splice site selection Chromatin modifications affect splice site recognition Transcription factor binding at regulatory elements can influence splicing patterns
Understanding RNA splicing defects in neurodegeneration has opened new therapeutic avenues[@rigo2024]:
Antisense oligonucleotides (ASOs): ASOs can be designed to:
AAV-mediated delivery: Viral vectors can deliver:
TDP-43 targets: ASOs designed to reduce TDP-43 aggregation or enhance its nuclear localization
FUS targets: Strategies to prevent FUS cytoplasmic aggregation
C9orf72 targets: ASOs targeting the expanded repeat to reduce toxic RNA and dipeptide repeat proteins
Current research directions in RNA splicing and neurodegeneration include[@guo2024]:
RNA splicing defects represent a common pathogenic mechanism across multiple neurodegenerative diseases. The loss of normal splicing function due to protein aggregation, genetic mutations, or transcriptional dysregulation leads to widespread abnormalities in mRNA processing. These defects affect genes critical for neuronal survival, synaptic function, and protein quality control, creating a feed-forward loop of neurodegeneration. Understanding these mechanisms offers promising therapeutic targets for disease-modifying treatments.
Alternative splicing is critical for generating the molecular diversity required for complex neuronal functions. In the brain, hundreds of genes undergo neuron-specific alternative splicing to produce protein isoforms with distinct functional properties[@ding2024].
Neurexins and neuroligins are synapse-associated cell adhesion molecules with extensive alternative splicing. Multiple cassette exons in these genes produce isoforms that determine synaptic specificity and function. Dysregulation of neurexin/neuologin splicing contributes to synaptic dysfunction in neurodegeneration.
Ion channels including sodium channels (SCN8A, SCN2A), calcium channels (CACNA1A, CACNA1C), and potassium channels undergo alternative splicing to generate isoforms with distinct electrophysiological properties. Splicing alterations in these channels may contribute to neuronal hyperexcitability in ALS and other disorders.
Actin cytoskeleton regulators including ABRA, SMARCA2, and CDC42EP3 undergo alternative splicing that affects dendritic spine morphology and synaptic plasticity.
Neuronal activity influences alternative splicing through:
Calcium-dependent splicing factors: Calmodulin-dependent kinases and calcineurin regulate splicing factor localization and activity
Neural activity-regulated splicing: Activity-dependent exon inclusion in genes like NR2A (GRIN2A) and PKM (PKM) influences synaptic plasticity
Activity-dependent splice switching: Neuronal depolarization can rapidly alter splicing patterns through phosphorylation of splicing regulators
The assembly of the spliceosome is a highly regulated process that occurs in distinct stages[@wahl2024]:
Splicing factor phosphorylation is a key regulatory mechanism:
SR protein phosphorylation:
Mitochondrial dysfunction is a hallmark of neurodegeneration, and splicing defects contribute to this dysfunction[@gao2024]:
Nuclear-encoded mitochondrial proteins undergo splicing:
Genes involved in mitophagy undergo splicing:
The proteostasis network is affected by splicing defects:
Splicing alterations affect ER stress responses:
Autophagy-related genes undergo alternative splicing:
Molecular chaperones show splicing alterations:
C9orf72:
LRRK2:
Splicing biomarkers offer diagnostic potential:
Several neurodegenerative diseases are caused by mutations in spliceosome components[@ferrari2024]:
SRSF2 mutations:
HNRNPA1/HNRNPA2B1:
Beyond splicing, other RNA processing steps are affected in neurodegeneration:
ADAR-mediated editing:
mRNA decay factors:
Transport granules:
Early neurodevelopmental splicing programs may influence adult neurodegeneration:
Developmental regulation of splicing factors:
Multiple therapeutic approaches target splicing[@rigo2024]:
Splice-switching oligonucleotides:
Spliceosome-targeting drugs:
Splice site editing:
SMN (survival motor neuron) deficiency caused by SMN1 loss of function leads to spinal muscular atrophy. SMN2, a paralog, undergoes aberrant splicing that produces truncated protein. This understanding led to splice-targeting therapies:
Spinraza (nusinersen): ASO promoting SMN2 exon 7 inclusion Onasemnogene abeparvovec: Gene therapy delivering SMN1 Risdiplam: Small molecule splice modulator
splicing defects in photoreceptor genes cause retinitis pigmentosa. Over 100 mutations affect splicing of genes including RHO, USH2A, and PRPF31. Therapeutic approaches include ASOs and CRISPR.
Alternative splicing of PMP22 (peripheral myelin protein 22) causes the most common form of CMT1A. Understanding this splicing defect has informed therapeutic development.
RNA-seq studies reveal:
Splicing regulatory networks:
Shared splicing defects across diseases:
Several critical questions remain[@guo2024]: