Loss of the thyroid hormone-binding protein Crym renders striatal neurons more vulnerable to mutant huntingtin in Huntington's disease.
The mechanisms underlying preferential atrophy of the striatum in Huntington's disease (HD) are unknown. One hypothesis is that a set of gene products preferentially expressed in the striatum could determine the particular vulnerability of this brain region to mutant huntingtin (mHtt). Here, we studied the striatal protein µ-crystallin (Crym). Crym is the NADPH-dependent p38 cytosolic T3-binding protein (p38CTBP), a key regulator of thyroid hormone (TH) T3 (3,5,3'-triiodo-l-thyronine) transportation. It has been also recently identified as the enzyme that reduces the sulfur-containing cyclic ketimines, which are potential neurotransmitters. Here, we confirm the preferential expression of the Crym protein in the rodent and macaque striatum. Crym expression was found to be higher in the macaque caudate than in the putamen. Expression of Crym was reduced in the BACHD and Knock-in 140CAG mouse models of HD before onset of striatal atrophy. We show that overexpression of Crym in striatal medium-size spiny neurons using a lentiviral-based strategy in mice is neuroprotective against the neurotoxicity of an N-terminal fragment of mHtt in vivo. Thus, reduction of Crym expression in HD could render striatal neurons more susceptible to mHtt suggesting that Crym may be a key determinant of the vulnerability of the striatum. In addition our work points to Crym as a potential molecular link between striatal degeneration and the THs deregulation reported in HD patients.
CEA, DSV, I²BM, Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France, Neurodegenerative Diseases Laboratory, CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France.
Laetitia
L
Francelle
CEA, DSV, I²BM, Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France, Neurodegenerative Diseases Laboratory, CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France.
Laurie
L
Galvan
CEA, DSV, I²BM, Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France, Neurodegenerative Diseases Laboratory, CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France.
Marie-Claude
MC
Gaillard
CEA, DSV, I²BM, Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France, Neurodegenerative Diseases Laboratory, CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France.
Martine
M
Guillermier
CEA, DSV, I²BM, Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France, Neurodegenerative Diseases Laboratory, CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France.
Diane
D
Houitte
CEA, DSV, I²BM, Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France, Neurodegenerative Diseases Laboratory, CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France.
Gilles
G
Bonvento
CEA, DSV, I²BM, Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France, Neurodegenerative Diseases Laboratory, CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France.
Fanny
F
Petit
CEA, DSV, I²BM, Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France, Neurodegenerative Diseases Laboratory, CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France.
Caroline
C
Jan
CEA, DSV, I²BM, Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France, Neurodegenerative Diseases Laboratory, CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France.
Noëlle
N
Dufour
CEA, DSV, I²BM, Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France, Neurodegenerative Diseases Laboratory, CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France.
Philippe
P
Hantraye
CEA, iBiTecS, F-91191 Gif-sur-Yvette Cedex, France, CNRS, FRE 3377, F-91191 Gif-sur-Yvette Cedex, France, Université Paris-Sud, FRE 3377, F-91191 Gif-sur-Yvette Cedex, France.
Jean-Marc
JM
Elalouf
CEA, iBiTecS, F-91191 Gif-sur-Yvette Cedex, France, CNRS, FRE 3377, F-91191 Gif-sur-Yvette Cedex, France, Université Paris-Sud, FRE 3377, F-91191 Gif-sur-Yvette Cedex, France.
Michel
M
De Chaldée
CEA, DSV, I²BM, Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France, Neurodegenerative Diseases Laboratory, CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France, Laboratory of Cellular and Molecular Neurotherapies, Department of Clinical Neurociences, Lausanne University Hospital, Lausanne, Switzerland.
Nicole
N
Déglon
CEA, DSV, I²BM, Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France, Neurodegenerative Diseases Laboratory, CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France, emmanuel.brouillet@cea.fr.
Emmanuel
E
Brouillet
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology*; D003459:Crystallins / Q000235:genetics*; D004195:Disease Models, Animal; D015536:Down-Regulation; D015870:Gene Expression; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology*; D008251:Macaca; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051381:Rats; D000090803:mu-Crystallins
C000716469:CRYM protein, human; C000716470:Crym protein, mouse; C000716471:Crym protein, rat; D003459:Crystallins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D000090803:mu-Crystallins