Repeated Repeat Problems: Combinatorial Effect of C9orf72-derived Dipeptide Repeat Proteins

Document Type

Article

Publication Date

2019

Keywords

ALSamyotrophic lateral sclerosis, amyotrophic lateral sclerosis, CDcircular dichroism, circular dichroism, CNScentral nervous system, central nervous system, DAPI4′, 6-diamidino-2-phenylindole, 4′, 6-diamidino-2-phenylindole, DLSdynamic light scattering, dynamic light scattering, DMEMDulbecco's modified eagle medium, Dulbecco's modified eagle medium, DPRdipeptide repeat protein, dipeptide repeat protein, EDTAethlenediaminetetraacetic acid, ethlenediaminetetraacetic acid, ERendoplasmic reticulum, endoplasmic reticulum, FBSfetal bovine serum, fetal bovine serum, FTDfrontotemporal dementia, frontotemporal dementia, HREhexanucleotide repeat expansion, hexanucleotide repeat expansion, IPTGisopropyl β-d-1-thiogalactopyranoside, isopropyl β-d-1-thiogalactopyranoside, ITCisothermal titration calorimetry, isothermal titration calorimetry, LCDlow complexity domain, low complexity domain, PBSphosphate-buffered saline, phosphate-buffered saline, PERKprotein kinase R(PKR)-like endoplasmic reticulum kinase, protein kinase R(PKR)-like endoplasmic reticulum kinase, PMSFphenylmethane sulfonyl fluoride or phenylmethylsulfonyl fluoride, phenylmethane sulfonyl fluoride or phenylmethylsulfonyl fluoride, poly(GA)dipeptide repeat protein consisting of glycine-alanine dipeptide repeats, dipeptide repeat protein consisting of glycine-alanine dipeptide repeats, poly(GP)dipeptide repeat protein consisting of glycine-proline dipeptide repeats, dipeptide repeat protein consisting of glycine-proline dipeptide repeats, poly(GR)dipeptide repeat protein consisting of glycine-arginine dipeptide repeats, dipeptide repeat protein consisting of glycine-arginine dipeptide repeats, poly(PA)dipeptide repeat protein consisting of proline-alanine dipeptide repeats, dipeptide repeat protein consisting of proline-alanine dipeptide repeats, poly(PR)dipeptide repeat protein consisting of proline-arginine dipeptide repeats, dipeptide repeat protein consisting of proline-arginine dipeptide repeats, RANrepeat-associated non-ATG translation, repeat-associated non-ATG translation, SDS-PAGEsodium dodecyl sulfate polyacrylamide gel electrophoresis, sodium dodecyl sulfate polyacrylamide gel electrophoresis, TBSTris-buffered saline, Tris-buffered saline, TEMtransmission electron microscopy, transmission electron microscopy, C9orf72, Dipeptide repeat protein, ALS, FTD, Poly(GA), Poly(PR), Intrinsically disordered proteins

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.ijbiomac.2019.01.035

Abstract

A microsatellite expansion mutation in C9orf72 is the most common genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). The expansion mutation leads to C9orf72 loss of function, RNA foci formation, and generation of five species of non-AUG RAN translated dipeptide repeat proteins (DPRs), such as poly(GA), poly(GP), poly(GR), poly(PA), and poly(PR). Although one cell can contain more than type of DPRs, information about interplay between different DPR species is limited. Here we show that the combined expression of distinct C9orf72-derived dipeptide repeat species produces cellular outcomes and structural differences that are unique compared to the expression of a single DPR species, suggesting the complex biological interactions that occur when multiple DPR variants are simultaneously expressed. Our data highlights the need for further analysis of how combined expression of different DPRs affects the disease state.

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Yes

Citation / Publisher Attribution

International Journal of Biological Macromolecules, v. 127, p. 136-145

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