Delayed Onset and Reduced Cognitive Deficits through Pre-Conditioning with 3-Nitropropionic Acid is Dependent on Sex and CAG Repeat Length in the R6/2 Mouse Model of Huntington’s Disease

2016 ◽  
Vol 5 (1) ◽  
pp. 19-32 ◽  
Author(s):  
Elizabeth A. Skillings ◽  
A. Jennifer Morton
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cognitive Deficits ◽  
Repeat Length ◽  
Cag Repeat ◽  
Delayed Onset ◽  
Nitropropionic Acid ◽  
3 Nitropropionic Acid

294 Neurofilament light protein as a biomarker for huntington’s disease

2018 ◽  
Vol 89 (10) ◽  
pp. A46.2-A46
Author(s):  
Byrne Lauren ◽  
Rodrigues Filipe ◽  
Johnson Eileanoir ◽  
Solyu Kucharz Rana ◽  
Gregory Sarah ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurological Diseases ◽  
Repeat Length ◽  
Cag Repeat ◽  
Neurofilament Light ◽  
Potential Biomarker ◽  
Clinical Measures ◽  
Motor Onset

BackgroundNeurofilament light protein (NfL), a component of the axonal cytoskeleton, has been shown to be increased in cerebrospinal fluid (CSF) and blood and to respond to successful treatment in several neurological diseases. We set out to investigate NfL as a potential biomarker for Huntington’s disease (HD).MethodsWe studied NfL in plasma from 298 participants, in plasma and CSF in 37 participants, and in the R6/2 HD mouse model.ResultsNfL concentration was increased in plasma at every stage of HD including premanifest mutation carriers, rose with progression and had a striking relationship with HTT CAG repeat length. In premanifest HD, baseline plasma NfL predicted subsequent motor onset even after adjustment for age and CAG repeat length. NfL predicted clinical, cognitive and neuroimaging progression, and CSF and plasma levels were strongly associated (Byrne et al, Lancet Neurology 2017). VBM analysis revealed that NfL level predicted atrophy throughout the white matter and in the occipital grey matter (Johnson et al, Neurology 2018). In the R6/2 mouse model, NfL was increased in plasma and CSF and associated with brain volume and clinical measures (Soylu Kucharz et al, Scientific Reports 2017).ConclusionsNfL is a promising clinical and translational biomarker for HD.

Rutin and Selenium Co-administration Reverse 3-Nitropropionic Acid-Induced Neurochemical and Molecular Impairments in a Mouse Model of Huntington’s Disease

2019 ◽  
Vol 37 (1) ◽  
pp. 77-92 ◽  
Author(s):  
Mohamed S. Abdelfattah ◽  
Sherif E. A. Badr ◽  
Sally A. Lotfy ◽  
Gouda H. Attia ◽  
Ahmed M. Aref ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Nitropropionic Acid ◽  
3 Nitropropionic Acid

scholarly journals A critical window of CAG repeat-length correlates with phenotype severity in the R6/2 mouse model of Huntington's disease

2012 ◽  
Vol 107 (2) ◽  
pp. 677-691 ◽  
Author(s):  
Damian M. Cummings ◽  
Yasaman Alaghband ◽  
Miriam A. Hickey ◽  
Prasad R. Joshi ◽  
S. Candice Hong ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Age At Onset ◽  
Human Condition ◽  
Repeat Length ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Drug Trials ◽  
Electrophysiological Properties

The R6/2 mouse is the most frequently used model for experimental and preclinical drug trials in Huntington's disease (HD). When the R6/2 mouse was first developed, it carried exon 1 of the huntingtin gene with ∼150 cytosine-adenine-guanine (CAG) repeats. The model presented with a rapid and aggressive phenotype that shared many features with the human condition and was particularly similar to juvenile HD. However, instability in the CAG repeat length due to different breeding practices has led to both decreases and increases in average CAG repeat lengths among colonies. Given the inverse relationship in human HD between CAG repeat length and age at onset and to a degree, the direct relationship with severity of disease, we have investigated the effect of altered CAG repeat length. Four lines, carrying ∼110, ∼160, ∼210, and ∼310 CAG repeats, were examined using a battery of tests designed to assess the basic R6/2 phenotype. These included electrophysiological properties of striatal medium-sized spiny neurons, motor activity, inclusion formation, and protein expression. The results showed an unpredicted, inverted “U-shaped” relationship between CAG repeat length and phenotype; increasing the CAG repeat length from 110 to 160 exacerbated the R6/2 phenotype, whereas further increases to 210 and 310 CAG repeats greatly ameliorated the phenotype. These findings demonstrate that the expected relationship between CAG repeat length and disease severity observed in humans is lost in the R6/2 mouse model and highlight the importance of CAG repeat-length determination in preclinical drug trials that use this model.

A Bile Acid Protects against Motor and Cognitive Deficits and Reduces Striatal Degeneration in the 3-Nitropropionic Acid Model of Huntington's Disease

2001 ◽  
Vol 171 (2) ◽  
pp. 351-360 ◽  
Author(s):  
C.Dirk Keene ◽  
Cecilia M.P. Rodrigues ◽  
Tacjana Eich ◽  
Cheryle Linehan-Stieers ◽  
Anna Abt ◽  
...  
Keyword(s):  
Bile Acid ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cognitive Deficits ◽  
Nitropropionic Acid ◽  
Striatal Degeneration ◽  
3 Nitropropionic Acid

scholarly journals The Association between CAG Repeat Length and Age of Onset of Juvenile-Onset Huntington’s Disease

2020 ◽  
Vol 10 (9) ◽  
pp. 575 ◽  
Author(s):  
Jordan L. Schultz ◽  
Amelia D. Moser ◽  
Peg C. Nopoulos
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Age Of Onset ◽  
Repeat Length ◽  
Cag Repeat ◽  
Linear Regression Models ◽  
Juvenile Onset ◽  
Additional Information ◽  
Using Data ◽  
The Relationship

There is a known negative association between cytosine–adenine–guanine (CAG) repeat length and the age of motor onset (AMO) in adult-onset Huntington’s Disease (AOHD). This relationship is less clear in patients with juvenile-onset Huntington’s disease (JOHD), however, given the rarity of this patient population. The aim of this study was to investigate this relationship amongst a relatively large group of patients with JOHD using data from the Kids-JOHD study. Additionally, we analyzed data from the Enroll-HD platform and the Predict-HD study to compare the relationship between CAG repeat length and AMO amongst patients with AOHD to that amongst patients with JOHD using linear regression models. In line with previous reports, the variance in AMO that was predicted by CAG repeat length was 59% (p < 0.0001) in the Predict-HD study and 57% from the Enroll-HD platform (p < 0.0001). However, CAG repeat length predicted 84% of the variance in AMO amongst participants from the Kids-JOHD study (p < 0.0001). These results indicate that there may be a stronger relationship between CAG repeat length and AMO in patients with JOHD as compared to patients with AOHD. These results provide additional information that may help to model disease progression of JOHD, which is beneficial for the planning and implementation of future clinical trials.

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