Microsatellite expansion disorders: Molecular mechanisms and therapeutic targets

More than 50 neurological diseases are caused by microsatellite repeat expansions, including myotonic dystrophy, C9ORF72 amyotrophic lateral sclerosis/ frontotemporal dementia (C9-ALS/FTD), and Huntington disease (HD). The molecular mechanisms of these diseases have traditionally been categorized based on the location of the mutations within coding or non-coding regions of their corresponding genes. The discoveries of bidirectional transcription of microsatellite expansion mutations and repeat-associated non-AUG (RAN) translation add further mechanistic complexity to these disorders and raises the possibility that one or both expansion transcripts and up to six RAN proteins contribute to many of these diseases. Significant advances have made in understanding molecular mechanisms underlying various repeat disorders and many therapeutic strategies targeting different pathways have been developed, including antisense oligonucleotides (ASO), small molecules, antibody therapies, and CRISPR/Cas9 technologies.

For this Research Topic, we will focus on microsatellite repeat expansion mutations especially those located in non-coding regions of their corresponding genes, including established disorders such as DM1, DM2, C9orf72 ALS/FTD, SCA8, and FXTAS, as well as newer disorders such as NIID, OPDM, and BAFME. Although substantial progress has been made in this field, additional experiments are needed to better understand the scope and mechanisms of disease and to develop novel therapeutic targets. First, it is important to understand how these diseases arise, how prevalent they are amongst patients with unknown genetic etiologies, and what role repeat instability plays in disease. Second, additional studies that define contributions of sense and antisense transcripts to pathogenesis in individual repeat expansion disease are needed. Given the sequence flanking the repeat tracts differs dramatically between disease loci, it will also be important to determine what mechanistic features are shared between different repeat expansion diseases. Third, it is important to understand the molecular factors that are required for RAN translation and to understand whether the mechanisms vary depending on the availability or absence of close-cognate codons, RNA secondary structures, and stress pathways. Fourth, therapeutic strategies targeting various mechanisms associated with repeat expansion mutations are needed and may lead to therapies that can turn off pathogenic pathways common to multiple microsatellite expansion disorders.

In this Research Topic, we welcome submissions of original research, review, clinical trial, brief research report, hypothesis and theory, and mini review articles covering the following themes:

• Identification of novel repeat expansions in human disease
• Contributions of sense and antisense repeat-containing transcripts to disease
• Mechanisms and implications of RAN translation in neurodegenerative disease
• Cell culture and animal models that recapitulate the pathological and behavioral features of repeat expansion diseases
• Instability of microsatellite repeat expansions
• Effects of epigenetic modifications on the expression of sense and antisense transcripts as well as RAN translation.
• Developments of therapeutic approaches that mitigate RNA-mediated and/or RAN protein-mediated toxicity.
• Biomarkers for diagnosis and treatment of repeat expansion disorders.
• Clinical trials

Expected manuscripts related to the 'Neurogenomics' section include articles dealing with multiple omics technologies including genomics, transcriptomics, proteomics, epigenomics, and phosphoproteomics.

Dr. Zu and Dr. Ranum have patents pending on RAN translation and RAN proteins. All other topic editors declare no competing interests with regards to the Research Topic subject.