TY - JOUR
T1 - Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity
AU - Zhang, Yong Jie
AU - Guo, Lin
AU - Gonzales, Patrick K.
AU - Gendron, Tania F.
AU - Wu, Yanwei
AU - Jansen-West, Karen
AU - O’Raw, Aliesha D.
AU - Pickles, Sarah R.
AU - Prudencio, Mercedes
AU - Carlomagno, Yari
AU - Gachechiladze, Mariam A.
AU - Ludwig, Connor
AU - Tian, Ruilin
AU - Chew, Jeannie
AU - DeTure, Michael
AU - Lin, Wen Lang
AU - Tong, Jimei
AU - Daughrity, Lillian M.
AU - Yue, Mei
AU - Song, Yuping
AU - Andersen, Jonathan W.
AU - Castanedes-Casey, Monica
AU - Kurti, Aishe
AU - Datta, Abhishek
AU - Antognetti, Giovanna
AU - McCampbell, Alexander
AU - Rademakers, Rosa
AU - Oskarsson, Björn
AU - Dickson, Dennis W.
AU - Kampmann, Martin
AU - Ward, Michael E.
AU - Fryer, John D.
AU - Link, Christopher D.
AU - Shorter, James
AU - Petrucelli, Leonard
N1 - Funding Information:
We are grateful to all patients who agreed to donate postmortem tissue. This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [grants R35NS097273 (L.P.), P01NS084974 (L.P., D.W. D., R.R., and B.O.), P01NS099114 (T.F.G. and L.P.), R01NS088689 (L.P.), R01NS063964 (C.D.L.), and U54NS100717 (M.K.)]; the National Institutes of Health National Institute on Aging [grants R01AG062359 and R56AG057528 (M.K.)]; the National Institutes of Health National Institute of General Medical Sciences [grant DP2GM119139 (M.K.)]; the Mayo Clinic Foundation (L.P.); the Amyotrophic Lateral Sclerosis Association (T.F.G., L.P., Y.-J.Z., and M.P.); the Robert Packard Center for ALS Research at Johns Hopkins (L.P. and J.S.); and the Target ALS Foundation (T.F.G., L.G., L.P., J.S., and Y.-J.Z.).
PY - 2019/2/15
Y1 - 2019/2/15
N2 - How hexanucleotide GGGGCC (G 4 C 2 ) repeat expansions in C9orf72 cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded G 4 C 2 repeats. The expression of green fluorescent protein–conjugated (PR) 50 (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1a (HP1a) liquid-phase disruptions, decreases in HP1a expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1a, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. Thus, we uncovered mechanisms by which poly(PR) may contribute to the pathogenesis of C9orf72-associated FTD and ALS.
AB - How hexanucleotide GGGGCC (G 4 C 2 ) repeat expansions in C9orf72 cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded G 4 C 2 repeats. The expression of green fluorescent protein–conjugated (PR) 50 (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1a (HP1a) liquid-phase disruptions, decreases in HP1a expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1a, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. Thus, we uncovered mechanisms by which poly(PR) may contribute to the pathogenesis of C9orf72-associated FTD and ALS.
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U2 - 10.1126/science.aav2606
DO - 10.1126/science.aav2606
M3 - Article
C2 - 30765536
AN - SCOPUS:85061562727
VL - 363
JO - Science
JF - Science
SN - 0036-8075
IS - 6428
M1 - eaav2606
ER -