How Short Tandem Repeats Elicit Neurologic Disease
Instability and expansion at more than 60 different short tandem repeat loci in our genomes are associated with human disease. We study the mechanisms by which these repeats elicit neuronal dysfunction and neurodegeneration. Repeats as DNA impact the transcription of the genes in which they reside- which can lead to gene silencing or activation. Once transcribed, the repeats as RNA can sequester proteins and prevent them from doing their normal jobs. Repeats also trigger translation of toxic proteins through an unusual process known as RAN translation that is a central area of study in the lab. In many conditions, repeats act through multiple mechanisms simultaneously as DNA, RNA and protein which makes therapy development complex.
Mechanisms of Repeat-Associated non-AUG (RAN) Translation
Repeats surprisingly can support translational initiation in the absence of an AUG start codon. We have studied this process over the past decade. Sometimes RAN translation begins like canonical initiation with cap binding and scanning along the mRNA. However, the repeat serves as a roadblock that slows scanning and encourages use of codons that are almost AUG- such as ACG or CUG- as initiation codons. At the same time, initiation in some cases occurs through direct engagement of the ribosome with repeat RNA through a more mysterious process known as internal ribosome entry. Once initiated, the repeats can also trigger translational frameshifts to create chimeric peptides that accumulate in pathologic inclusions. We are actively developing novel strategies to target each of these mechanisms with the hope that such interventions will mitigate neurodegeneration in repeat expansion disorders.
Image: Malik et al, Nat Cell Mol Rev 2021
Fragile X-Associated Disorders
CGG repeat expansions in the FMR1 gene can cause multiple clinical disorders. Very large expansions silence the gene so that little or no fragile X protein (FMRP) is produced. This causes Fragile X Syndrome, which is the most common single gene cause of autism and intellectual disability. More intermediate CGG expansions in FMR1 (known as “premutations” do something different: they boost transcription of the repeat RNA, which then binds to proteins as RNA and gets translated into toxic peptides through RAN translation. The end result is development of a late onset neurodegenerative disease known as Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) or an genetic cause of early menopause known as Fragile X-associated premature ovarian insufficiency (FXPOI). Our group studies all these conditions and is developing novel therapies for FXTAS in particular. We also are helping to lead clinical trials in this space (see clinical research section).
From Tassone et al, Cells, 2025
C9orf72 FTD and ALS
An intronic GGGGCC repeat is the most common single gene cause of both Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Our group has described how transcriptional initiation within the intron “exonizes” the mRNA to allow for its translation. We have also shown how the integrated stress response activates RAN translation of this mRNA and how ribosomal quality control pathways alter the rates of RAN translation. Most recently we have characterized how protein translation in neurons differs from other cells, which alters the mechanism used for RAN translation in neurons – with important clinical implications.
From Miller et al, PNAS 2025
RFC1 repeat expansions and CANVAS
A biallelic non-reference AAGGG repeat expansion in the DNA repair gene RFC1 is among the most common causes of both idiopathic sensory neuropathy and cerebellar ataxia as well as a syndromic condition known as Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS). This condition remains a mystery, it is unclear how the repeat elicits disease given that expression of the RFC1 protein remains normal in patients. We are using iPSC derived neurons, cellular and mouse models to explore how this repeat elicits disease with the hope of designing effective treatments for patients.
From Maltby et al, Science Advances 2024
Understanding the native functions of short tandem repeats
Working with collaborators both at Michigan and elsewhere, we are identifying novel repeat expansions associated with neurological disorders – including where repeats serve as risk alleles for more common conditions. We are also exploring how the same repeat in different loci (or sometimes in the same loci) can elicit such disparate phenotypes. At the same time, we are exploring what native functions repeats may have in neuronal plasticity and how repeat evolution may reflect both positive and negative selection pressures in humans and primates.
From Wright et al, eLife, 2023