scholarly journals A Progressive Loss of phosphoSer138-Profilin Aligns with Symptomatic Course in the R6/2 Mouse Model of Huntington’s Disease: Possible Sex-Dependent Signaling

2020 ◽  
Author(s):  
Akanksha Baharani ◽  
Zelan Wei ◽  
William J. Roesler ◽  
Darrell D. Mousseau
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Activity Patterns ◽  
Cag Repeat ◽  
Signaling Cascades ◽  
Actin Binding ◽  
Rac Gtpase ◽  
Cytoskeleton Organization ◽  
Healthy Control

Abstract The R6/2 transgenic mouse model of Huntington’s disease (HD) carries several copies of exon1 of the huntingtin gene that contains a highly pathogenic 120 CAG-repeat expansion. We used kinome analysis to screen for kinase activity patterns in neural tissues from wildtype (WT) and R6/2 mice at a pre-symptomatic (e.g., embryonic) and symptomatic (e.g., between 3 and 10 weeks postnatal) time points. We identified changes in several signaling cascades, for example, the Akt/FoxO3/CDK2, mTOR/ULK1, and RAF/MEK/CREB pathways. We also identified the Rho-Rac GTPase cascade that contributes to cytoskeleton organization through modulation of the actin-binding proteins, cofilin and profilin. Immunoblotting revealed higher levels of phosphoSer138-profilin in embryonic R6/2 mouse samples (cf. WT mice) that diminish progressively and significantly over the postnatal, symptomatic course of the disease. We detected sex- and genotype-dependent patterns in the phosphorylation of actin-regulators such a ROCK2, PAK, LIMK1, cofilin, and SSH1L, yet none of these aligned consistently with the changing levels of phosphoSer138-profilin. This could be reflecting an imbalance in the sequential influences these regulators are known to exert on actin signaling. The translational potential of these observations was inferred from preliminary observations of changes in LIMK-cofilin signaling and loss of neurite integrity in neural stem cells derived from an HD patient (versus a healthy control). Our observations suggest that a pre-symptomatic, neurodevelopmental onset of change in the phosphorylation of Ser138-profilin, potentially downstream of distinct signaling changes in male and female mice, could be contributing to cytoskeletal phenotypes in the R6/2 mouse model of HD pathology.

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.

scholarly journals Latent Toxoplasma gondii infection increases soluble mutant huntingtin and promotes neurodegeneration in the YAC128 mouse model of Huntington’s disease

2019 ◽  
Author(s):  
David W. Donley ◽  
Teal Jenkins ◽  
Cailin Deiter ◽  
Reed Campbell ◽  
Marley Realing ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Latent Infection ◽  
Neurodegenerative Disorder ◽  
Cag Repeat ◽  
Mutant Huntingtin ◽  
Large Variability ◽  
Yac128 Mouse

AbstractToxoplasma gondii causes a prevalent neuroinvasive protozoal pathogen that in immune competent individuals results in latent infection characterized by intra-cellular parasite cysts in brain. Despite life-long infection, the role of latent toxoplasmosis on chronic neurodegenerative processes is poorly understood. Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a dominant CAG repeat expansion in the huntingtin gene (HTT) that results in the expression and accumulation of mutant huntingtin protein (mHTT). The mutant HD gene is fully penetrant. However, there is significant variability in disease progression that is in part explained by as yet unidentified environmental factors. The kynurenine pathway of tryptophan metabolism (KP) is an inflammatory pathway and its activation is implicated in HD pathogenesis. KP upregulation also occurs in response to infection with Toxoplasma gondii suggesting that the latent infection may promote HD. We discovered that mice on the FVB/NJ background develop latent toxoplasmosis following infection with the ME49 strain of T. gondii. This finding enabled us to address the hypothesis that latent toxoplasmosis potentiates disease in the YAC128 mouse model of HD, as these mice are maintained on the FVB/NJ background. Wild-type and HD mice were infected at 2-months of age. During the 10-month follow-up, infection had adverse effects on mice of both genotypes. However, YAC128 HD mice demonstrated specific vulnerability to latent toxoplasmosis, as demonstrated by the presence of increased striatal degeneration, high levels of the blood neurodegeneration marker neurofilament light protein, and elevated brain soluble mHTT. Our studies have uncovered a novel HD-infection interaction in mice that provides insights into the large variability of the human HD phenotype.

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.

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