C9orf72-Related Neurodegenerative Diseases: From Clinical Diagnosis to Therapeutic Strategies

Abstract

Hexanucleotide expansion in C9orf72 has been related to several phenotypes to date, complicating the clinical recognition of these neurodegenerative disorders. An early diagnosis can improve the management of patients, promoting early administration of therapeutic supportive strategies. Here, we report known clinical presentations of C9orf72-related neurodegenerative disorders, pointing out suggestive phenotypes that can benefit the genetic characterization of patients. Considering the high variability of C9orf72-related disorder, frequent and rare manifestations are described, with detailed clinical, instrumental evaluation, and supportive therapeutical approaches. Furthermore, to improve the understanding of molecular pathways of the disease and potential therapeutical targets, a detailed description of the cellular mechanisms related to the pathological effect of C9orf72 is reported. New promising therapeutical strategies and ongoing studies are reported highlighting their molecular role in cellular pathological pathways of C9orf72. These therapeutic approaches are particularly promising because they seem to stop the disease before neuronal damage. The knowledge of clinical and molecular features of C9orf72-related neurodegenerative disorders improves the therapeutical application of known strategies and will lay the basis for the development of new potential therapies.

Keywords: ALS; C9orf72; FTD; molecular mechanisms; neurodegeneration; therapeutic strategies.

Figure 1

Physiological and pathological molecular mechanisms linked to C9orf72 expansion. Normal alleles lead to the production of three mRNA (V1, V2, and V3), translated into two C9 isoforms (long and short; Smeyers et al., 2021). High-repeat expansion (HRE) C9orf72 alleles lead to four different pathological mechanisms: (i) hypermethylation of DNA and intron retention in mRNA leading to haploinsufficiency; (ii) DNA G-quadruplexes and R-loop formation leading to activation of DNA repair damage response and somaticmosaicism; (iii) RNA foci formation, with intramolecular (stem-loop, and G-quadruplexes) and intermolecular (RNA-RNA, RNA-RNA-binding protein (RBP), and RBP-RBP) interactions (Malik et al., 2021), leading to RBP sequestration and reduced cellular translation; (iv) RAN translation of sense and antisense mRNAs produces five different DPRs (polyGA, polyGR, polyGP, polyPR, and polyPA). Drugs of which it is known or supposed molecular function are reported: metformin reduces RAN translation, LAM-002A interferes with DPRs formation, WVE-004 and BIIB078 promotes the degradation of C9orf72 expanded mRNAs, TPN-101 reduces the DNA repair damage response.