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

• Published in: Neurobiology of aging Vol. 46; pp. 192 - 203
• Main Authors: Gami-Patel, Priya, Bandopadhyay, Rina, Brelstaff, Jack, Revesz, Tamas, Lashley, Tammaryn
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2016
• Subjects: Active Transport, Cell Nucleus; Adult; Aged; Aged, 80 and over; beta Karyopherins - metabolism; beta Karyopherins - physiology; Female; FET proteins; Frontotemporal dementia; Frontotemporal Lobar Degeneration - metabolism; FUS; Heterogeneous Nuclear Ribonucleoprotein A1; Heterogeneous-Nuclear Ribonucleoprotein Group A-B - metabolism; Heterogeneous-Nuclear Ribonucleoproteins - metabolism; hnRNP; Humans; Inclusion Bodies - metabolism; Internal Medicine; Male; Middle Aged; NanoString; Neurites - metabolism; Neurology; Protein Transport; RNA-Binding Protein FUS - metabolism; Transportin; frontotemporal dementia; hnRNP; nanostring; FUS; FET proteins; transportin; NanoString; Frontotemporal dementia; Transportin
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2016.07.004

Abstract Frontotemporal lobar degeneration with FUS-positive inclusions (FTLD-FUS) is a disease with unknown cause. Transportin1 (TRN1) 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 TRN1-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. Biochemical analysis revealed a shift in the location of hnRNP A1 from the nucleus to the cytoplasm. 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.