TY - JOUR
T1 - Huntingtin proteolysis releases non-polyQ fragments that cause toxicity through dynamin 1 dysregulation
AU - El-Daher, Marie Thérèse
AU - Hangen, Emilie
AU - Bruyère, Julie
AU - Poizat, Ghislaine
AU - Al-Ramahi, Ismael
AU - Pardo, Raul
AU - Bourg, Nicolas
AU - Souquere, Sylvie
AU - Mayet, Céline
AU - Pierron, Gérard
AU - Lévêque-Fort, Sandrine
AU - Botas, Juan
AU - Humbert, Sandrine
AU - Saudou, Frédéric
N1 - Publisher Copyright:
© 2015 The Authors.
PY - 2015/9/2
Y1 - 2015/9/2
N2 - Cleavage of mutant huntingtin (HTT) is an essential process in Huntington's disease (HD), an inherited neurodegenerative disorder. Cleavage generates N-ter fragments that contain the polyQ stretch and whose nuclear toxicity is well established. However, the functional defects induced by cleavage of full-length HTT remain elusive. Moreover, the contribution of non-polyQ C-terminal fragments is unknown. Using time- and site-specific control of full-length HTT proteolysis, we show that specific cleavages are required to disrupt intramolecular interactions within HTT and to cause toxicity in cells and flies. Surprisingly, in addition to the canonical pathogenic N-ter fragments, the C-ter fragments generated, that do not contain the polyQ stretch, induced toxicity via dilation of the endoplasmic reticulum (ER) and increased ER stress. C-ter HTT bound to dynamin 1 and subsequently impaired its activity at ER membranes. Our findings support a role for HTT on dynamin 1 function and ER homoeostasis. Proteolysis-induced alteration of this function may be relevant to disease. Synopsis The development of a time and site-specifically controlled cleavage of the mutant huntingtin protein reveals a pathogenic mechanism induced by the non-polyQ-containing fragments that are generated upon proteolysis during disease progression. Huntingtin proteolysis generates N-ter fragments that contain the toxic polyQ stretch but also the corresponding C-ter fragments. N-ter to C-ter intramolecular interactions present in full-length huntingtin are abrogated by sequential cleavages. Whereas the N-ter polyQ fragments translocate into the nucleus, the non-polyQ C-ter huntingtin fragments remain in the cytoplasm and cause ER dilation, stress and cell death. C-ter huntingtin fragments bind and inactivate dynamin 1 at the ER thus causing ER dilation and toxicity. Site-specifically controlled cleavage of the mutant huntingtin protein reveals a pathogenic mechanism induced by non-polyQ-containing fragments that are generated upon proteolysis during disease progression.
AB - Cleavage of mutant huntingtin (HTT) is an essential process in Huntington's disease (HD), an inherited neurodegenerative disorder. Cleavage generates N-ter fragments that contain the polyQ stretch and whose nuclear toxicity is well established. However, the functional defects induced by cleavage of full-length HTT remain elusive. Moreover, the contribution of non-polyQ C-terminal fragments is unknown. Using time- and site-specific control of full-length HTT proteolysis, we show that specific cleavages are required to disrupt intramolecular interactions within HTT and to cause toxicity in cells and flies. Surprisingly, in addition to the canonical pathogenic N-ter fragments, the C-ter fragments generated, that do not contain the polyQ stretch, induced toxicity via dilation of the endoplasmic reticulum (ER) and increased ER stress. C-ter HTT bound to dynamin 1 and subsequently impaired its activity at ER membranes. Our findings support a role for HTT on dynamin 1 function and ER homoeostasis. Proteolysis-induced alteration of this function may be relevant to disease. Synopsis The development of a time and site-specifically controlled cleavage of the mutant huntingtin protein reveals a pathogenic mechanism induced by the non-polyQ-containing fragments that are generated upon proteolysis during disease progression. Huntingtin proteolysis generates N-ter fragments that contain the toxic polyQ stretch but also the corresponding C-ter fragments. N-ter to C-ter intramolecular interactions present in full-length huntingtin are abrogated by sequential cleavages. Whereas the N-ter polyQ fragments translocate into the nucleus, the non-polyQ C-ter huntingtin fragments remain in the cytoplasm and cause ER dilation, stress and cell death. C-ter huntingtin fragments bind and inactivate dynamin 1 at the ER thus causing ER dilation and toxicity. Site-specifically controlled cleavage of the mutant huntingtin protein reveals a pathogenic mechanism induced by non-polyQ-containing fragments that are generated upon proteolysis during disease progression.
KW - Drosophila
KW - ER dilation
KW - Huntington's disease
KW - TEV proteolysis
KW - endoplasmic reticulum
UR - http://www.scopus.com/inward/record.url?scp=84940640081&partnerID=8YFLogxK
U2 - 10.15252/embj.201490808
DO - 10.15252/embj.201490808
M3 - Article
C2 - 26165689
AN - SCOPUS:84940640081
SN - 0261-4189
VL - 34
SP - 2255
EP - 2271
JO - EMBO Journal
JF - EMBO Journal
IS - 17
ER -