PMID- 30343032
OWN - NLM
STAT- MEDLINE
DCOM- 20191121
LR  - 20191121
IS  - 1095-953X (Electronic)
IS  - 0969-9961 (Linking)
VI  - 121
DP  - 2019 Jan
TI  - Pharmacological enhancement of retinoid-related orphan receptor alpha function 
      mitigates spinocerebellar ataxia type 3 pathology.
PG  - 263-273
LID - S0969-9961(18)30730-7 [pii]
LID - 10.1016/j.nbd.2018.10.014 [doi]
AB  - Cerebellar Purkinje cells (PCs) are the sole output neurons of the cerebellar 
      cortex, and damage to PCs results in motor deficits. Spinocerebellar ataxia type 
      3 (SCA3, also known as Machado-Joseph disease), a hereditary neurodegenerative 
      disease, is caused by an abnormal expansion of the polyglutamine tract in the 
      causative ATXN3 protein. SCA3 affects a wide range of cells in the central 
      nervous system, including those in the cerebellum. To unravel SCA3 pathology, we 
      used adeno-associated virus serotype 9 (AAV9) vectors to express full-length 
      ATXN3 with an abnormally expanded 89 polyglutamine stretch (ATXN3[Q89]) in 
      cerebellar neurons of mature wild-type mice. Mice expressing ATXN3[Q89] exhibited 
      motor impairment in a manner dependent on the viral titer. Immunohistochemistry 
      of the cerebellum showed ubiquitinated nuclear aggregates in PCs; degeneration of 
      PC dendrites; and a significant decrease in multiple proteins including 
      retinoid-related orphan receptor alpha (RORalpha), a transcription factor, and type 1 
      metabotropic glutamate receptor (mGluR1) signaling molecules. Patch clamp 
      analysis of ATXN3[Q89]-expressing PCs revealed marked defects in mGluR1 
      signaling. Notably, the emergence of behavioral, morphological, and functional 
      defects was inhibited by a single injection of SR1078, an RORalpha/gamma agonist. These 
      results suggest that RORalpha plays a key role in mutant ATXN3-mediated aberrant 
      phenotypes and that the pharmacological enhancement of RORalpha could function as a 
      method for therapeutic intervention in SCA3.
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Watanave, Masashi
AU  - Watanave M
AD  - Department of Neurophysiology & Neural Repair, Gunma University Graduate School 
      of Medicine, Maebashi, Gunma 371-8511, Japan.
FAU - Hoshino, Chiaki
AU  - Hoshino C
AD  - Department of Neurophysiology & Neural Repair, Gunma University Graduate School 
      of Medicine, Maebashi, Gunma 371-8511, Japan.
FAU - Konno, Ayumu
AU  - Konno A
AD  - Department of Neurophysiology & Neural Repair, Gunma University Graduate School 
      of Medicine, Maebashi, Gunma 371-8511, Japan.
FAU - Fukuzaki, Yumi
AU  - Fukuzaki Y
AD  - Department of Neurophysiology & Neural Repair, Gunma University Graduate School 
      of Medicine, Maebashi, Gunma 371-8511, Japan.
FAU - Matsuzaki, Yasunori
AU  - Matsuzaki Y
AD  - Department of Neurophysiology & Neural Repair, Gunma University Graduate School 
      of Medicine, Maebashi, Gunma 371-8511, Japan.
FAU - Ishitani, Tohru
AU  - Ishitani T
AD  - Institute for Molecular & Cellular Regulation, Gunma University, Maebashi, Gunma 
      371-8511, Japan.
FAU - Hirai, Hirokazu
AU  - Hirai H
AD  - Department of Neurophysiology & Neural Repair, Gunma University Graduate School 
      of Medicine, Maebashi, Gunma 371-8511, Japan. Electronic address: 
      hirai@gunma-u.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181019
PL  - United States
TA  - Neurobiol Dis
JT  - Neurobiology of disease
JID - 9500169
RN  - 0 (Nuclear Receptor Subfamily 1, Group F, Member 1)
RN  - 0 (Peptides)
RN  - 0 (Receptors, Metabotropic Glutamate)
RN  - 0 (Repressor Proteins)
RN  - 0 (Rora protein, mouse)
RN  - 0 (metabotropic glutamate receptor type 1)
RN  - 26700-71-0 (polyglutamine)
RN  - EC 3.4.19.12 (ATXN3 protein, human)
RN  - EC 3.4.19.12 (Ataxin-3)
SB  - IM
MH  - Animals
MH  - Ataxin-3/genetics/*metabolism
MH  - Dendrites/pathology
MH  - Humans
MH  - Machado-Joseph Disease/*metabolism/pathology
MH  - Mice, Inbred C57BL
MH  - Nuclear Receptor Subfamily 1, Group F, Member 1/*metabolism
MH  - Peptides/genetics
MH  - Protein Aggregation, Pathological/metabolism
MH  - Purkinje Cells/*metabolism/pathology
MH  - Receptors, Metabotropic Glutamate/metabolism
MH  - Repressor Proteins/genetics/*metabolism
MH  - Signal Transduction
OTO - NOTNLM
OT  - AAV vector
OT  - Cerebellum
OT  - Machado-Joseph disease
OT  - Purkinje cell
OT  - Retinoid-related orphan receptor alpha
OT  - Slow excitatory postsynaptic current
OT  - Spinocerebellar ataxia type 3
OT  - Type 1 metabotropic glutamate receptor
EDAT- 2018/10/22 06:00
MHDA- 2019/11/22 06:00
CRDT- 2018/10/22 06:00
PHST- 2018/06/14 00:00 [received]
PHST- 2018/09/26 00:00 [revised]
PHST- 2018/10/17 00:00 [accepted]
PHST- 2018/10/22 06:00 [pubmed]
PHST- 2019/11/22 06:00 [medline]
PHST- 2018/10/22 06:00 [entrez]
AID - S0969-9961(18)30730-7 [pii]
AID - 10.1016/j.nbd.2018.10.014 [doi]
PST - ppublish
SO  - Neurobiol Dis. 2019 Jan;121:263-273. doi: 10.1016/j.nbd.2018.10.014. Epub 2018 
      Oct 19.