Abnormal scaffold attachment factor 1 expression and localization in spinocerebellar ataxias and Huntington's chorea.

Nicola Buckner,Oscar Cordero-Llana,Andriana Gialeli,Nicholas Allen,Alastair Wilkins,Helen L Scott,Liang-Fong Wong,James B Uney,Caroline Rivers,Gongyu Shi,Kevin C Kemp

doi:10.1111/bpa.12872

Nicola Buckner, Oscar Cordero-Llana + Show 9 more

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https://doi.org/10.1111/bpa.12872

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Journal: Brain Pathology	Publication Date: Jul 13, 2020
Citations: 3	License type: CC BY 4.0

Affiliation: University of Bristol, Cardiff University

Abstract

SAFB1 is a DNA and RNA binding protein that is highly expressed in the cerebellum and hippocampus and is involved in the processing of coding and non‐coding RNAs, splicing and dendritic function. We analyzed SAFB1 expression in the post‐mortem brain tissue of spinocerebellar ataxia (SCA), Huntington’s disease (HD), Multiple sclerosis (MS), Parkinson’s disease patients and controls. In SCA cases, the expression of SAFB1 in the nucleus was increased and there was abnormal and extensive expression in the cytoplasm where it co‐localized with the markers of Purkinje cell injury. Significantly, no SAFB1 expression was found in the cerebellar neurons of the dentate nucleus in control or MS patients; however, in SCA patients, SAFB1 expression was increased significantly in both the nucleus and cytoplasm of dentate neurons. In HD, we found that SAFB1 expression was increased in the nucleus and cytoplasm of striatal neurons; however, there was no SAFB1 staining in the striatal neurons of controls. In PD substantia nigra, we did not see any changes in neuronal SAFB1 expression. iCLIP analysis found that SAFB1 crosslink sites within ATXN1 RNA were adjacent to the start and within the glutamine repeat sequence. Further investigation found increased binding of SAFB1 to pathogenic ATXN1‐85Q mRNA. These novel data strongly suggest SAFB1 contributes to the etiology of SCA and Huntington’s chorea and that it may be a pathological marker of polyglutamine repeat expansion diseases.

Highlights

RNA binding proteins (RBPs) play an important regulatory role in cellular metabolism by defining the complex interactions of coding, structural and regulatory RNA species [23]
As Scaffold attachment factor B1 (SAFB1) shares properties with RBPs known to be implicated in human neurodegenerative disease, is expressed at high levels in the cerebellum, translocates to nuclear stress bodies following the exposure of cells to a variety of stresses and binds ATXN1 we investigated its expression in spinocerebellar ataxia (SCA) alongside other neurodegenerative diseases
Immunohistochemical characterization of SAFB1 expression was carried out in cerebellar tissue from patients diagnosed with SCA and compared to the cerebellum from control primary antibody was negative (Figure S1)

Summary

Introduction

RNA binding proteins (RBPs) play an important regulatory role in cellular metabolism by defining the complex interactions of coding, structural and regulatory RNA species [23]. As neurons are post-mitotic and have highly complex transcriptomes, they will be susceptible to the changes in gene regulation brought about by altered RBP function. This hypothesis is supported by recent findings suggesting that altered RBP function contributes to the death of neurons seen in polyglutamine (polyQ) expansion diseases (e.g. spinocerebellar ataxia type 1 (SCA1) and Huntington’s disease (HD)) [4,25]. The sequestration of RBPs by the translated mutant proteins has been shown to contribute to pathology due to a loss and/or toxic gain of RBP function Mutations in the RBPs, TDP-43 [14], FUS [43] and MATR3 [13] have been found to cause ALS directly linking altered RBP function in the etiology of human neurodegenerative illnesses

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