dystonia
J Neurosci. 2005 Nov 9;25(45):10502-9. Exp Neurol. 2005 Dec;196(2):452-63.
Epub 2005 Oct 20. J Mol Neurosci. 2005;25(1):105-17. J Med
Genet. 2006 May;43(5):394-400. Epub 2005 Oct 14. Parkinsonism
Relat Disord.
2006 Jan;12(1):15-9. Epub
2005 Sep 29.
Silencing primary dystonia: lentiviral-mediated
RNA interference therapy for DYT1 dystonia.
Gonzalez-Alegre
P, Bode
N, Davidson
BL, Paulson
HL.
Department of Neurology, Carver College of Medicine, University of Iowa,
Iowa City, Iowa 52242, USA. pedro-gonzalez-alegre@uiowa.edu
DYT1 is the most common inherited dystonia.
Currently, there are no preventive or curative therapies for this
dominantly inherited disease. DYT1 dystonia is
caused by a common three-nucleotide deletion in the TOR1A gene that
eliminates a glutamic acid residue from the
protein torsinA. Recent studies suggest that torsinA carrying the disease-linked mutation, torsinA(DeltaE) acts through a dominant-negative effect by
recruiting wild-type torsinA [torsinA(wt)]
into oligomeric structures in the nuclear
envelope. Therefore, suppressing torsinA(DeltaE) expression through
RNA interference (RNAi) could restore the normal
function of torsinA(wt), representing a
potentially effective therapy regardless of the biological role of torsinA. Here, we have generated short hairpin RNAs (shRNAs) that mediate
allele-specific suppression of torsinA(DeltaE) and rescue cells from
its dominant-negative effect, restoring the normal distribution of torsinA(wt). In addition, delivery of this shRNA by a recombinant feline immunodeficiency virus effectively
silenced torsinA(DeltaE) in a neural model of
the disease. We further establish the feasibility of this viral-mediated RNAi approach by demonstrating significant suppression
of endogenous torsinA in mammalian neurons.
Finally, this silencing of torsinA is achieved
without triggering an interferon response. These results support the
potential use of viral-mediated RNAi as a therapy
for DYT1 dystonia and establish the basis for
preclinical testing in animal models of the disease.
PMID: 16280588 [PubMed - indexed for MEDLINE]
Generation and characterization of Dyt1 DeltaGAG knock-in mouse as a model for early-onset dystonia.
Dang
MT, Yokoi
F, McNaught KS, Jengelley TA, Jackson
T, Li
J, Li
Y.
Department of Molecular and Integrative Physiology, NeuroTech Group, Beckman Institute for Advanced Science
and Technology,
A trinucleotide deletion of GAG in the DYT1 gene
that encodes torsinA protein is implicated in the
neurological movement disorder of Oppenheim's early-onset
dystonia. The mutation removes a glutamic acid in the carboxy
region of torsinA, a member of the Clp protease/heat shock protein family. The function of
torsinA and the role of the mutation in causing dystonia are largely unknown. To gain insight into
these unknowns, we made a gene-targeted mouse model of Dyt1 DeltaGAG to mimic the mutation found in DYT1 dystonic patients. The mutated heterozygous mice had
deficient performance on the beam-walking test, a measure of fine motor
coordination and balance. In addition, they exhibited hyperactivity in the
open-field test. Mutant mice also showed a gait abnormality of increased
overlap. Mice at 3 months of age did not display deficits in beam-walking
and gait, while 6-month mutant mice did, indicating an age factor in
phenotypic expression as well. While striatal
dopamine and 4-dihydroxyphenylacetic acid (DOPAC) levels in Dyt1 DeltaGAG mice were similar to that of wild-type mice, a
27% decrease in 4-hydroxy, 3-methoxyphenacetic acid (homovanillic
acid) was detected in mutant mice. Dyt1 DeltaGAG
tissues also have ubiquitin- and torsinA-containing aggregates in neurons of the pontine nuclei. A sex difference was noticed in the
mutant mice with female mutant mice exhibiting fewer alterations in
behavioral, neurochemical, and cellular changes.
Our results show that knocking in a Dyt1 DeltaGAG
allele in mouse alters their motor behavior and recapitulates the
production of protein aggregates that are seen in dystonic
patients. Our data further support alterations in the dopaminergic
system as a part of dystonia's neuropathology.
PMID: 16242683 [PubMed - indexed for MEDLINE]
Dystonia-associated forms of torsinA
are deficient in ATPase activity.
Konakova
M, Pulst
SM.
Rose Moss Laboratory for Parkinson's Disease and
Neurodegenerative Disorders, Burns and Allen Research Institute,
Early-onset dystonia is caused by mutations in
the torsinA protein, a putative member of the
AAA+ class of ATPases. In this study we have
evaluated the ATPase activity of bacterially expressed
wild-type torsinA and its disease-associated
mutant forms. Upon overexpression in Escherichia
coli, recombinant torsinA proteins were
accumulated as insoluble inclusion bodies and required refolding to become
soluble and catalytically active. The refolded wild-type and mutant torsinA proteins were capable of hydrolyzing ATP, but
their specific ATPase activities differed
significantly. Deletions of the amino acid residues E302/303 and F323-Y328
resulted in a decrease of ATPase activity to
approximately 35% and approximately 75% of the wild-type level,
respectively. ATPase activity of wild-type and
mutant torsinA proteins was influenced by factors
that varied with cell stress, such as temperature, pH, and ionic strength,
and was inhibited by sodium vanadate. Our results
provide the first direct evidence for a role of torsinA
as an active ATPase and suggest that the
mutations in torsinA might affect normal
functions of the protein by reducing its enzymatic activity.
PMID: 15781971 [PubMed - indexed for MEDLINE]
Epsilon sarcoglycan mutations and phenotype in French patients
with myoclonic syndromes.
Tezenas
du Montcel S, Clot
F, Vidailhet
M, Roze
E, Damier
P, Jedynak
CP, Camuzat
A, Lagueny
A, Vercueil
L, Doummar
D, Guyant-Marechal
L, Houeto
JL, Ponsot
G, Thobois
S, Cournelle
MA, Durr
A, Durif
F, Echenne
B, Hannequin
D, Tranchant
C, Brice
A; French
Dystonia Network.
Service de Biostatistique et
Information Medicale, Hopital
Pitie-Salpetriere, AP-HP,
BACKGROUND: Myoclonus dystonia
syndrome (MDS) is an autosomal dominant movement
disorder caused by mutations in the epsilon-sarcoglycan
gene (SGCE) on chromosome 7q21. METHODS: We have screened for SGCE
mutations in index cases from 76 French patients with myoclonic
syndromes, including myoclonus dystonia (M-D), essential myoclonus
(E-M), primary myoclonic dystonia,
generalised dystonia, dystonia with tremor, and benign hereditary chorea. All
coding exons of the SGCE gene were analysed. The DYT1 mutation was also tested. RESULTS:
Sixteen index cases had SGCE mutations while one case with primary myoclonic dystonia carried
the DYT1 mutation. Thirteen different mutations were found: three nonsense
mutations, three missense mutations, three splice
site mutations, three deletions, and one insertion. Eleven of the SGCE
index cases had M-D and five E-M. No SGCE
mutations were detected in patients with other phenotypes. The total number
of mutation carriers in the families was 38, six of whom were asymptomatic.
Penetrance was complete in paternal transmissions
and null in maternal transmissions. MDS patients with SGCE mutation had a
significantly earlier onset than the non-carriers. None of the patients had
severe psychiatric disorders. CONCLUSION: This large cohort of index
patients shows that SGCE mutations are primarily found in patients with M-D
and to a lesser extent E-M, but are present in only 30% of these patients
combined (M-D and E-M).
PMID: 16227522 [PubMed - in process]
DYT1 mutation in a
cohort of Taiwanese primary dystonias.
Lin
YW, Chang
HC, Chou
YH, Chen
RS, Hsu
WC, Wu
WS, Weng YH, Lu
CS.
Movement Disorders Unit, Department of Neurology,
To investigate the DYT1 gene mutation in Chinese ethnic, we examined a
series of 200 patients with primary dystonias (11
familial and 189 sporadic), 53 of their asymptomatic relatives, 97 patients
with familial or early-onset parkinsonism, and 200
healthy subjects. The GAG deletion at codon 946
was only found in three sporadic dystonia
patients and seven of their asymptomatic familial members. The frequency of
GAG deletion was 1.5% in dystonia patients, and
was 6.7% in early-onset dystonias (< or = 26
years). We conclude that DYT1 mutation is a minor cause of primary dystonias in a cohort of Taiwanese population.
PMID: 16198613 [PubMed - indexed for MEDLINE