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Review
. 2023 Jul 27;12(15):1948.
doi: 10.3390/cells12151948.

Studies of Genetic and Proteomic Risk Factors of Amyotrophic Lateral Sclerosis Inspire Biomarker Development and Gene Therapy

Eva Bagyinszky  1 , John Hulme  1 , Seong Soo A An  2
Affiliations
Review

Studies of Genetic and Proteomic Risk Factors of Amyotrophic Lateral Sclerosis Inspire Biomarker Development and Gene Therapy

Eva Bagyinszky et al. Cells. .

Abstract

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease affecting the upper and lower motor neurons, leading to muscle weakness, motor impairments, disabilities and death. Approximately 5-10% of ALS cases are associated with positive family history (familial ALS or fALS), whilst the remainder are sporadic (sporadic ALS, sALS). At least 50 genes have been identified as causative or risk factors for ALS. Established pathogenic variants include superoxide dismutase type 1 (SOD1), chromosome 9 open reading frame 72 (c9orf72), TAR DNA Binding Protein (TARDBP), and Fused In Sarcoma (FUS); additional ALS-related genes including Charged Multivesicular Body Protein 2B (CHMP2B), Senataxin (SETX), Sequestosome 1 (SQSTM1), TANK Binding Kinase 1 (TBK1) and NIMA Related Kinase 1 (NEK1), have been identified. Mutations in these genes could impair different mechanisms, including vesicle transport, autophagy, and cytoskeletal or mitochondrial functions. So far, there is no effective therapy against ALS. Thus, early diagnosis and disease risk predictions remain one of the best options against ALS symptomologies. Proteomic biomarkers, microRNAs, and extracellular vehicles (EVs) serve as promising tools for disease diagnosis or progression assessment. These markers are relatively easy to obtain from blood or cerebrospinal fluids and can be used to identify potential genetic causative and risk factors even in the preclinical stage before symptoms appear. In addition, antisense oligonucleotides and RNA gene therapies have successfully been employed against other diseases, such as childhood-onset spinal muscular atrophy (SMA), which could also give hope to ALS patients. Therefore, an effective gene and biomarker panel should be generated for potentially "at risk" individuals to provide timely interventions and better treatment outcomes for ALS patients as soon as possible.

Keywords: amyotrophic lateral sclerosis; biomarkers; diagnosis; genetic factors; proteomic markers; therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Pathological processes that may contribute to neuronal death in MND and ALS.
Figure 2
Figure 2
Mutant SOD1 and ALS-related pathways, adapted from Refs. [20,21,27].
Figure 3
Figure 3
TARDBP mechanisms in ALS progression, adapted from Refs. [46,47,48].
Figure 4
Figure 4
Domains of FUS gene and possible mechanisms of FUS mutations, adapted from Refs. [50,51].
Figure 5
Figure 5
Activation of neurodegenerative pathways resulting from C9orf72 repeat expansion. Repeat expansion could be associated with loss-of function (LOF) mechanism, called haploinsufficiency. Gain-of function (GOF)mechanisms may also be related with G4C2 expansion, such as RNA-Binding Proteins (RBP) sequestration (leading to alternative splicing and impaired RNA transport/translation). Additional GOF pathway could be an alternative START codon generation and Repeat Associated Non-AUG (RAN) translation, leading to dipeptide repeat (DPR) production, accumulation and toxicity. The figure was adapted from Refs. [66,67,68,69,70,71,72,73].
Figure 6
Figure 6
Potential biological processes/functions affected by common and rare ALS-related genes during ALS progression [18,74]. The differently colored edges may represent the proterin-protein associations. The light blue means, association was verified from curated databases. Pink means, interactions were proven experimentally. The darker green means “gene neighbourhood”. Red means possible gene fusion. Darker blue means gene co-occurrence. Light green means “text mining” or possible association from literature. The black means that the genes may interact through co-expression. The purple edge means that these genes may share homology. Network analyses were performed by STRING software version 11.5 (https://string-db.org/, accessed on 20 July 2023).
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References

    1. Masrori P., Van Damme P. Amyotrophic lateral sclerosis: A clinical review. Eur. J. Neurol. 2020;27:1918–1929. doi: 10.1111/ene.14393. - DOI - PMC - PubMed
    1. Hulisz D. Amyotrophic lateral sclerosis: Disease state overview. Am. J. Manag. Care. 2018;24((Suppl. S15)):S320–S326. - PubMed
    1. Ravits J.M., La Spada A.R. ALS motor phenotype heterogeneity, focality, and spread: Deconstructing motor neuron degeneration. Neurology. 2009;73:805–811. doi: 10.1212/WNL.0b013e3181b6bbbd. - DOI - PMC - PubMed
    1. Testa D., Lovati R., Ferrarini M., Salmoiraghi F., Filippini G. Survival of 793 patients with amyotrophic lateral sclerosis diagnosed over a 28-year period. Amyotroph. Lateral Scler. Other Mot. Neuron Disord. 2004;5:208–212. doi: 10.1080/14660820410021311. - DOI - PubMed
    1. Logroscino G., Traynor B.J., Hardiman O., Chiò A., Mitchell D., Swingler R.J., Millul A., Benn E., Beghi E., Eurals F. Incidence of amyotrophic lateral sclerosis in Europe. J. Neurol. Neurosurg. Psychiatry. 2010;81:385–390. doi: 10.1136/jnnp.2009.183525. - DOI - PMC - PubMed

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Grants and funding

This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education NRF-2020R1A2B5B01002463, and 2021R1A6A1A03038996.