Abstract
Neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), Parkinson’s, Alzheimer’s, and Huntington’s disease affect a rapidly increasing population worldwide. Although common pathogenic mechanisms have been identified (e.g., protein aggregation or dysfunction, immune response alteration and axonal degeneration), the molecular events underlying timing, dosage, expression, and location of RNA molecules are still not fully elucidated. In particular, the alternative splicing (AS) mechanism is a crucial player in RNA processing and represents a fundamental determinant for brain development, as well as for the physiological functions of neuronal circuits. Although in recent years our knowledge of AS events has increased substantially, deciphering the molecular interconnections between splicing and ALS remains a complex task and still requires considerable efforts. In the present review, we will summarize the current scientific evidence outlining the involvement of AS in the pathogenic processes of ALS. We will also focus on recent insights concerning the tuning of splicing mechanisms by epigenomic and epi-transcriptomic regulation, providing an overview of the available genomic technologies to investigate AS drivers on a genome-wide scale, even at a single-cell level resolution. In the future, gene therapy strategies and RNA-based technologies may be utilized to intercept or modulate the splicing mechanism and produce beneficial effects against ALS.
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Abbreviations
- ALS:
-
Amyotrophic lateral sclerosis
- AS:
-
Alternative splicing
- RBPs:
-
RNA-binding proteins
- fALS:
-
Familial amyotrophic lateral sclerosis
- sALS:
-
Sporadic amyotrophic lateral sclerosis
- FTD:
-
Frontotemporal dementia
- ES:
-
Exon skipping
- IR:
-
Intron retention
- C9:
-
C9ORF72
- snRNA:
-
Small nuclear RNA
- snRNPs:
-
Small nuclear ribonucleoproteins
- PPIases:
-
Peptidyl-propyl cis/trans isomerases
- ESEs:
-
Exonic splicing enhancers
- ISEs:
-
Intronic splicing enhancers
- ESSs:
-
Exonic splicing silencers
- ISSs:
-
Intronic splicing silencers
- PrLD:
-
Prion-like domain
- hnRNP:
-
Heterogenous nuclear ribonucleoprotein
- PTB:
-
Polypyrimidine tract-binding protein
- MN:
-
Motoneuron
- SMaRT:
-
Transcription of spliceosome-mediated RNA
- siRNA:
-
Small interfering RNA
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Acknowledgements
The authors gratefully acknowledge the projects “Un approccio diagnostico multidisciplinare per le malattie neurodegenerative dell’invecchiamento” (DSB.AD009.001) and “Life Analytics, human centric platform per la salute ed il benessere dell’uomo” (DSB.AD008.456), and Angelo Bagalà, Ariangela Belvedere, Benedetto Bruno, Walter Carpino, Tiziana Martire, and Patrizia Rizzuto for their administrative and technical support.
Funding
This work has been supported by Grants: (i) “Un approccio diagnostico multidisciplinare per le malattie neurodegenerative dell’invecchiamento”, DSB.AD009.001; (ii) “Sviluppo ed applicazione di tecnologie biosensoristiche in Genomica” CIP 2014.IT.05.SFOP.014/3/10.4/9.2.10/0008, CUP G67B17000170009, n. 11/2017 “Rafforzare l’Occupabilità nel sistema R&S e la nascita di spin off di ricerca in Sicilia—PROGRAMMA OPERATIVO DEL FONDO SOCIALE EUROPEO REGIONE SICILIA 2014–2020”, and (iii) “Life Analytics, human centric platform per la salute ed il benessere dell’uomo”, DSB.AD008.456.
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BP and VLC reviewed the literature and wrote the manuscript. FLC participated in revising the manuscripts. TS, CU, SA provided critical inputs to the manuscript. SC conceived, directed, and supervised the project. All authors have read and approved the final version of this manuscript, and agreed to be accountable for all aspects of the work and consent for publication.
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Perrone, B., La Cognata, V., Sprovieri, T. et al. Alternative Splicing of ALS Genes: Misregulation and Potential Therapies. Cell Mol Neurobiol 40, 1–14 (2020). https://doi.org/10.1007/s10571-019-00717-0
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DOI: https://doi.org/10.1007/s10571-019-00717-0