Journal Article

DZNE-2026-00386

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The insertion of an ATTTC repeat in an Alu element hyperactivates a neurodevelopmental enhancer in spinocerebellar ataxia type 37.

Loureiro, J. R. (First author)DZNE* ; Castro, A. F. ; Figueiredo, A. S. ; Eufrásio, A. ; Dhingra, A.DZNE* ; Galhardo, M. ; Marcelino, H. ; Rodrigues, C. C. ; Sampaio, P. ; Azevedo, M. ; Sousa, M. ; Dória, S. ; Rizzu, P.DZNE* ; Heutink, P.DZNE* ; Bessa, J. ; Silveira, I.

2026
Cell Press Maryland Heights, MO

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Please use a persistent id in citations: doi:10.1016/j.celrep.2026.117146

Abstract: Alu elements are evolutionarily very old primate-specific interspersed repeat elements that constitute ∼11% of the human genome. They are a source of short tandem repeats (STRs), which often expand in size and cause inherited neuromuscular and neurodegenerative disorders. How expanded STR insertion mutations within Alu STRs culminate in disease remains unknown. Here, we report an Alu STR located in an intron of DAB1 that functions as a neurodevelopmental enhancer. We demonstrate that an ATTTC repeat insertion in this DAB1 Alu STR, known to cause spinocerebellar ataxia type 37 (SCA37), hyperactivates a neurodevelopmental DAB1 enhancer. Importantly, we show that neurons derived from SCA37 subjects have higher levels of DAB1 expression and that DAB1 overexpression causes abnormal axonal pathfinding in vivo. Overall, these results establish that neuronal dysregulation of a developmental DAB1 Alu STR enhancer contributes to SCA37 pathogenesis, an unexplored mechanism likely acting in many Alu STR diseases, potentially reshaping the therapeutic landscape.

Keyword(s): 4C-seq ; CAGE ; CP: genomics ; CP: neuroscience ; DAB1 primate-specific Alu element ; SCA37 ; STR ; axonal pathfinding ; cap analysis of gene expression ; cerebellar transcriptional enhancer ; circularized chromosome conformation capture sequencing ; iPSN ; neurodegenerative disease ; pentanucleotide repeat expansion ; short tandem repeat ; spinocerebellar ataxia type 37

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Contributing Institute(s):

1. Genome Biology of Neurodegenerative Diseases (AG Heutink)
2. Applied Genomics for Neurodegenerative Diseases (AG Rizzu)

Research Program(s):

1. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)

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