Abstract
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a limited expansion of CGG repeats in the 5′ UTR of FMR1. Two mechanisms are proposed to cause FXTAS: RNA gain-of-function, where CGG RNA sequesters specific proteins, and translation of CGG repeats into a polyglycine-containing protein, FMRpolyG. Here we developed transgenic mice expressing CGG repeat RNA with or without FMRpolyG. Expression of FMRpolyG is pathogenic, while the sole expression of CGG RNA is not. FMRpolyG interacts with the nuclear lamina protein LAP2β and disorganizes the nuclear lamina architecture in neurons differentiated from FXTAS iPS cells. Finally, expression of LAP2β rescues neuronal death induced by FMRpolyG. Overall, these results suggest that translation of expanded CGG repeats into FMRpolyG alters nuclear lamina architecture and drives pathogenesis in FXTAS.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 331-347 |
| Number of pages | 17 |
| Journal | Neuron |
| Volume | 93 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 18 2017 |
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Keywords
- microsatellite expansion
- near-cognate codon
- neurodegeneration
- RAN translation
ASJC Scopus subject areas
- Neuroscience(all)
Cite this
Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome. / Sellier, Chantal; Buijsen, Ronald A M; He, Fang; Natla, Sam; Jung, Laura; Tropel, Philippe; Gaucherot, Angeline; Jacobs, Hugues; Meziane, Hamid; Vincent, Alexandre; Champy, Marie France; Sorg, Tania; Pavlovic, Guillaume; Wattenhofer-Donze, Marie; Birling, Marie Christine; Oulad-Abdelghani, Mustapha; Eberling, Pascal; Ruffenach, Frank; Joint, Mathilde; Anheim, Mathieu; Martinez-Cerdeno, Veronica; Tassone, Flora; Willemsen, Rob; Hukema, Renate K.; Viville, Stéphane; Martinat, Cecile; Todd, Peter K.; Charlet-Berguerand, Nicolas.
In: Neuron, Vol. 93, No. 2, 18.01.2017, p. 331-347.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome
AU - Sellier, Chantal
AU - Buijsen, Ronald A M
AU - He, Fang
AU - Natla, Sam
AU - Jung, Laura
AU - Tropel, Philippe
AU - Gaucherot, Angeline
AU - Jacobs, Hugues
AU - Meziane, Hamid
AU - Vincent, Alexandre
AU - Champy, Marie France
AU - Sorg, Tania
AU - Pavlovic, Guillaume
AU - Wattenhofer-Donze, Marie
AU - Birling, Marie Christine
AU - Oulad-Abdelghani, Mustapha
AU - Eberling, Pascal
AU - Ruffenach, Frank
AU - Joint, Mathilde
AU - Anheim, Mathieu
AU - Martinez-Cerdeno, Veronica
AU - Tassone, Flora
AU - Willemsen, Rob
AU - Hukema, Renate K.
AU - Viville, Stéphane
AU - Martinat, Cecile
AU - Todd, Peter K.
AU - Charlet-Berguerand, Nicolas
PY - 2017/1/18
Y1 - 2017/1/18
N2 - Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a limited expansion of CGG repeats in the 5′ UTR of FMR1. Two mechanisms are proposed to cause FXTAS: RNA gain-of-function, where CGG RNA sequesters specific proteins, and translation of CGG repeats into a polyglycine-containing protein, FMRpolyG. Here we developed transgenic mice expressing CGG repeat RNA with or without FMRpolyG. Expression of FMRpolyG is pathogenic, while the sole expression of CGG RNA is not. FMRpolyG interacts with the nuclear lamina protein LAP2β and disorganizes the nuclear lamina architecture in neurons differentiated from FXTAS iPS cells. Finally, expression of LAP2β rescues neuronal death induced by FMRpolyG. Overall, these results suggest that translation of expanded CGG repeats into FMRpolyG alters nuclear lamina architecture and drives pathogenesis in FXTAS.
AB - Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a limited expansion of CGG repeats in the 5′ UTR of FMR1. Two mechanisms are proposed to cause FXTAS: RNA gain-of-function, where CGG RNA sequesters specific proteins, and translation of CGG repeats into a polyglycine-containing protein, FMRpolyG. Here we developed transgenic mice expressing CGG repeat RNA with or without FMRpolyG. Expression of FMRpolyG is pathogenic, while the sole expression of CGG RNA is not. FMRpolyG interacts with the nuclear lamina protein LAP2β and disorganizes the nuclear lamina architecture in neurons differentiated from FXTAS iPS cells. Finally, expression of LAP2β rescues neuronal death induced by FMRpolyG. Overall, these results suggest that translation of expanded CGG repeats into FMRpolyG alters nuclear lamina architecture and drives pathogenesis in FXTAS.
KW - microsatellite expansion
KW - near-cognate codon
KW - neurodegeneration
KW - RAN translation
UR - http://www.scopus.com/inward/record.url?scp=85008501947&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85008501947&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2016.12.016
DO - 10.1016/j.neuron.2016.12.016
M3 - Article
C2 - 28065649
AN - SCOPUS:85008501947
VL - 93
SP - 331
EP - 347
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 2
ER -