30 Jun 2020

Massive genome-wide association studies for Alzheimer’s disease have primarily correlated genetic variants with clinical diagnosis, a rubric that is fraught with uncertainty. In a GWAS published June 22 in JAMA Neurology, researchers led by Timothy Hohman of Vanderbilt University Medical Center, Nashville, Tennessee, and Richard Mayeux of Columbia University Medical Center, New York, instead focused on the telltale pathological hallmark of early AD—amyloid plaques. The researchers tied common variants near the RBFOX1 gene to risk for amyloidosis among more than 4,000 people in the preclinical stage of the disease. Reduced expression of this RNA-binding protein correlated with higher Aβ burden in postmortem brain samples, where the protein was spotted mingling with plaques and in dystrophic neurites.

Co-first authors Neha Raghavan of Columbia and Logan Dumitrescu of Vanderbilt integrated genetic and amyloid-PET imaging data from 4,314 participants across six studies: the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (A4), the Alzheimer Disease Neuroimaging Initiative (ADNI), the Berkeley Aging Cohort Study, the Wisconsin Registry for Alzheimer’s Prevention (WRAP), the Biomarkers of Cognitive Decline Among Normal Individuals: the BIOCARD Cohort, and the Baltimore Longitudinal Study of Aging (BLSA). While some ADNI participants had mild cognitive impairment, those in other studies were cognitively normal.

The study confirmed previously reported associations between brain amyloidosis and ApoE4. In addition, 10 single-nucleotide variants within a novel locus that included the RBFOX1 gene significantly associated with Aβ accumulation at the genome-wide level in a meta-analysis of all cohorts.

To understand this association, the researchers investigated patterns of RBFOX1 expression in postmortem prefrontal cortex samples from the Religious Orders Study and Memory and Aging Project (ROS/MAP). Lower levels of RBFOX1 mRNA correlated with higher amyloid burden, steeper cognitive decline and, just prior to death, worse global cognition. Each standard deviation drop in RBFOX1 mRNA came with a 0.2-point drop on the mini mental state examination.

In control brains, the researchers detected the RBFOX1 protein in neurons. In AD brains, it was relegated to dystrophic neurites surrounding amyloid plaques, and also mingled with tau tangles.

Expression of the RNA-binding protein RBFOX1 was recently linked to variants in TMEM106b, a gene implicated in ALS/FTD. Christiane Reitz at Columbia links RBFOX1 to dementia incidence among black Americans in an upcoming paper (see Jun 2020 news). RBFOX1 also has been tied to brain glucose metabolism (Kong et al., 2018). 

As part of the Fox-1 family of RNA-binding proteins, RBFOX1 reportedly regulates alternative splicing and the stability of multiple mRNAs, and influences the development of neurons and synaptic networks (Auweter et al., 2006; Fogel et al., 2012; Hamada et al., 2015). RBFOX1 binds to ataxin-2, a protein implicated in spinocerebellar ataxia type 2, and variants in the gene have been tied to epilepsy, neurodevelopmental disorders, and aggressive behavior (Lal et al., 2013; Bill et al., 2013; Fernàndez-Castillo et al., 2020).—Jessica Shugart

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References

News Citations

1. TMEM106B Variants Regulate Gene Modules, TDP-43 Pathology 12 Jun 2020

Paper Citations

1. Kong LL, Miao D, Tan L, Liu SL, Li JQ, Cao XP, Tan L, Alzheimer’s Disease Neuroimaging Initiative*. Genome-wide association study identifies RBFOX1 locus influencing brain glucose metabolism. Ann Transl Med. 2018 Nov;6(22):436. PubMed.
2. Auweter SD, Fasan R, Reymond L, Underwood JG, Black DL, Pitsch S, Allain FH. Molecular basis of RNA recognition by the human alternative splicing factor Fox-1. EMBO J. 2006 Jan 11;25(1):163-73. Epub 2005 Dec 15 PubMed.
3. Fogel BL, Wexler E, Wahnich A, Friedrich T, Vijayendran C, Gao F, Parikshak N, Konopka G, Geschwind DH. RBFOX1 regulates both splicing and transcriptional networks in human neuronal development. Hum Mol Genet. 2012 Oct 1;21(19):4171-86. Epub 2012 Jun 23 PubMed.
4. Hamada N, Ito H, Iwamoto I, Morishita R, Tabata H, Nagata K. Role of the cytoplasmic isoform of RBFOX1/A2BP1 in establishing the architecture of the developing cerebral cortex. Mol Autism. 2015;6:56. Epub 2015 Oct 20 PubMed.
5. Lal D, Trucks H, Møller RS, Hjalgrim H, Koeleman BP, de Kovel CG, Visscher F, Weber YG, Lerche H, Becker F, Schankin CJ, Neubauer BA, Surges R, Kunz WS, Zimprich F, Franke A, Illig T, Ried JS, Leu C, Nürnberg P, Sander T, EMINet Consortium, EPICURE Consortium. Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy. Epilepsia. 2013 Feb;54(2):265-71. Epub 2013 Jan 25 PubMed.
6. Bill BR, Lowe JK, Dybuncio CT, Fogel BL. Orchestration of neurodevelopmental programs by RBFOX1: implications for autism spectrum disorder. Int Rev Neurobiol. 2013;113:251-67. PubMed.
7. Fernàndez-Castillo N, Gan G, van Donkelaar MM, Vaht M, Weber H, Retz W, Meyer-Lindenberg A, Franke B, Harro J, Reif A, Faraone SV, Cormand B. RBFOX1, encoding a splicing regulator, is a candidate gene for aggressive behavior. Eur Neuropsychopharmacol. 2020 Jan;30:44-55. Epub 2017 Nov 23 PubMed.

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