The presence of heterogeneous nuclear ribonucleoproteins in frontotemporal lobar degeneration with FUS-positive inclusions

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• 作者：Priya Gami-Patel ; Rina Bandopadhyay ; Jack Brelstaff ; Tamas Revesz ; Tammaryn Lashley ; ^{T.Lashley@ucl.ac.uk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Frontotemporal dementia ; FUS ; FET proteins ; hnRNP ; Transportin ; NanoString
• 刊名：Neurobiology of Aging
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：46
• 期：Complete
• 页码：192-203
• 全文大小：2120 K

文摘

Frontotemporal lobar degeneration with fused in sarcoma–positive inclusions (FTLD-FUS) is a disease with unknown cause. Transportin 1 is abundantly found in FUS-positive inclusions and responsible for the nuclear import of the FET proteins of which FUS is a member. The presence of all FET proteins in pathological inclusions suggests a disturbance of transportin 1–mediated nuclear import. FUS also belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) protein family. We investigated whether hnRNP proteins are associated with FUS pathology implicating dysfunctional nuclear export in the pathogenesis of FTLD-FUS. hnRNP proteins were investigated in affected brain regions in FTLD-FUS using immunohistochemistry, biochemical analysis, and the expression analysis. We demonstrated the presence of several hnRNP proteins in pathological inclusions including neuronal cytoplasmic inclusions and dystrophic neurites. The biochemical analysis revealed a shift in the location of hnRNP A1 from the nucleus to the cytoplasm. The expression analysis revealed an increase in several hnRNP proteins in FTLD-FUS. These results implicate a wider dysregulation of movement between intracellular compartments, than mechanisms only affecting the nuclear import of FUS proteins.