huntington disease
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2022 ◽  
Author(s):  
Carla Lopes ◽  
Ildete Luisa Ferreira ◽  
Carina Maranga ◽  
Margarida Beatriz ◽  
Sandra Mota ◽  
...  

Defects in mitochondrial function and mitochondrial-related redox deregulation have been attributed to Huntington disease (HD), a genetic neurodegenerative disorder largely affecting the striatum. However, whether these changes occur in early stages of the disease and can be detected in vivo is still unclear. Thus, in the present study, we analyzed changes in mitochondrial function and overreduced states associated with production of reactive oxygen species (ROS) at early stages and along disease progression in vivo in the brain by positron emission tomography (PET) and in skin fibroblasts of premanifest/early and manifest HD patients, and in YAC128 transgenic mouse brain (striatum and cortex) at early-symptomatic (3 month-old, mo) and symptomatic (6 to 12 mo) stages. In vivo human and mouse brain PET imaging was assessed using [64Cu]-ATSM; analysis of oxygen consumption rates was assessed by Seahorse analysis, hydrogen peroxide levels were determined using fluorescent probes and mitochondrial morphology by transmission electron microscopy in human skin fibroblasts and mouse striatal and cortical isolated mitochondria. Premanifest and prodromal HD carriers exhibited enhanced whole-brain (with exception of caudate) [64Cu]-ATSM labelling, correlating with CAG repeat number, concomitantly with enhanced basal and maximal respiration, proton (H+) leak and increased hydrogen peroxide levels, the later progressing to advanced HD stage, in human fibroblasts. Mitochondria from fibroblasts of premanifest HD carriers also showed reduced roundness, while higher number of mitochondrial DNA copies correlated with maximal respiratory capacity. In vivo animal PET analysis showed increased accumulation of [64Cu]-ATSM in YAC128 mouse striatum. Pre/early-symptomatic YAC128 mouse striatal, but not cortical, isolated mitochondria exhibited a rise in basal and maximal mitochondrial respiration and in ATP production along with increased complex II and III activities, enhanced mitochondrial hydrogen peroxide and roundness, as revealed by brain ultrastructure analysis, further presenting defects in Ca2+ handling, supporting increased striatal susceptibility in the YAC128 mouse model. Data demonstrate both human and mouse mitochondrial overactivity and altered morphology at early HD stages, facilitating redox unbalance, the latter extending over late disease stages.


2022 ◽  
Vol 12 (1) ◽  
pp. 36
Author(s):  
Simone Migliore ◽  
Giulia D’Aurizio ◽  
Eugenia Scaricamazza ◽  
Sabrina Maffi ◽  
Consuelo Ceccarelli ◽  
...  

We focused on Cognitive Reserve (CR) in patients with early Huntington Disease (HD) and investigated whether clinical outcomes might be influenced by lifetime intellectual enrichment over time. CR was evaluated by means of the Cognitive Reserve Index questionnaire (CRIq), an internationally validated scale which includes three sections: education, working activity, and leisure time. The clinical HD variables were quantified at three different time points (baseline-t0, 1 year follow up-t1 and 2 years follow up-t2) as per the Unified Huntington’s Disease Rating Scale (UHDRS), an internationally standardized and validated scale including motor, cognitive, functional and behavioral assays. Our sample consisted of 75 early manifest patients, withclinical stage scored according to the Total Functional Capacity (TFC) scale. Our correlational analysis highlighted a significant inverse association between CRIq leisure time (CRIq_LA) and longitudinal functional impairment (namely, the differential TFC score between t2 and t0 or ΔTFC) (p < 0.05), and the multidimensional progression of HD as measured by the composite UHDRS (cUHDRS, p < 0.01). CRIq_LA was significantly and positively associated with better cognitive performances at all time points (p < 0.05). Our results suggest that higher is the CRIq_LA, milder is the progression of HD in terms of functional, multidimensional and cognitive outcome.


Author(s):  
Marta Vela ◽  
María Adelaida García-Gimeno ◽  
Ana Sanchis ◽  
José Bono-Yagüe ◽  
José Cumella ◽  
...  

2021 ◽  
Author(s):  
Sergio de Armas-Rillo ◽  
Felipe Fumagallo-Reading ◽  
Diego Luis-Ravelo ◽  
Beatriz Abdul-Jalbar ◽  
Tomas Gonzalez-Hernandez ◽  
...  

2021 ◽  
Vol 87 ◽  
pp. 94-105
Author(s):  
Jordyn M. Wilcox ◽  
Anna C. Pfalzer ◽  
Adriana A. Tienda ◽  
Ines F. Debbiche ◽  
Ellen C. Cox ◽  
...  

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Kristina Bečanović ◽  
Muhammad Asghar ◽  
Izabella Gadawska ◽  
Shiny Sachdeva ◽  
David Walker ◽  
...  

2021 ◽  
Vol 33 (4) ◽  
pp. 293-300
Author(s):  
Larissa Arning ◽  
Huu Phuc Nguyen

Abstract The causative mutation for Huntington disease (HD), an expanded trinucleotide repeat sequence in the first exon of the huntingtin gene (HTT) is naturally polymorphic and inevitably associated with disease symptoms above 39 CAG repeats. Although symptomatic medical therapies for HD can improve the motor and non-motor symptoms for affected patients, these drugs do not stop the ongoing neurodegeneration and progression of the disease, which results in severe motor and cognitive disability and death. To date, there is still an urgent need for the development of effective disease‐modifying therapies to slow or even stop the progression of HD. The increasing ability to intervene directly at the roots of the disease, namely HTT transcription and translation of its mRNA, makes it necessary to understand the pathogenesis of HD as precisely as possible. In addition to the long-postulated toxicity of the polyglutamine-expanded mutant HTT protein, there is increasing evidence that the CAG repeat-containing RNA might also be directly involved in toxicity. Recent studies have identified cis- (DNA repair genes) and trans- (loss/duplication of CAA interruption) acting variants as major modifiers of age at onset (AO) and disease progression. More and more extensive data indicate that somatic instability functions as a driver for AO as well as disease progression and severity, not only in HD but also in other polyglutamine diseases. Thus, somatic expansions of repetitive DNA sequences may be essential to promote respective repeat lengths to reach a threshold leading to the overt neurodegenerative symptoms of trinucleotide diseases. These findings support somatic expansion as a potential therapeutic target in HD and related repeat expansion disorders.


2021 ◽  
Vol 34 (4) ◽  
pp. 295-302
Author(s):  
Rebecca K. Hendel ◽  
Marie N.N. Hellem ◽  
Lena E. Hjermind ◽  
Jørgen E. Nielsen ◽  
Asmus Vogel

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