scholarly journals Mitochondrial Respiration Changes in R6/2 Huntington’s Disease Model Mice during Aging in a Brain Region Specific Manner

2020 ◽  
Vol 21 (15) ◽  
pp. 5412 ◽  
Author(s):  
Johannes Burtscher ◽  
Alba Di Pardo ◽  
Vittorio Maglione ◽  
Christoph Schwarzer ◽  
Ferdinando Squitieri

Mitochondrial dysfunction is crucially involved in aging and neurodegenerative diseases, such as Huntington’s Disease (HD). How mitochondria become compromised in HD is poorly understood but instrumental for the development of treatments to prevent or reverse resulting deficits. In this paper, we investigate whether oxidative phosphorylation (OXPHOS) differs across brain regions in juvenile as compared to adult mice and whether such developmental changes might be compromised in the R6/2 mouse model of HD. We study OXPHOS in the striatum, hippocampus, and motor cortex by high resolution respirometry in female wild-type and R6/2 mice of ages corresponding to pre-symptomatic and symptomatic R6/2 mice. We observe a developmental shift in OXPHOS-control parameters that was similar in R6/2 mice, except for cortical succinate-driven respiration. While the LEAK state relative to maximal respiratory capacity was reduced in adult mice in all analyzed brain regions, succinate-driven respiration was reduced only in the striatum and cortex, and NADH-driven respiration was higher as compared to juvenile mice only in the striatum. We demonstrate age-related changes in respirational capacities of different brain regions with subtle deviations in R6/2 mice. Uncovering in situ oxygen conditions and potential substrate limitations during aging and HD disease progression are interesting avenues for future research to understand brain-regional vulnerability in HD.

2021 ◽  
Vol 11 (10) ◽  
pp. 1267
Author(s):  
Johannes Burtscher ◽  
Giuseppe Pepe ◽  
Federico Marracino ◽  
Luca Capocci ◽  
Susy Giova ◽  
...  

Huntington’s disease (HD) is a rare hereditary neurodegenerative disorder characterized by multiple metabolic dysfunctions including defects in mitochondrial homeostasis and functions. Although we have recently reported age-related changes in the respiratory capacities in different brain areas in HD mice, the precise mechanisms of how mitochondria become compromised in HD are still poorly understood. In this study, we investigated mRNA and protein levels of selected subunits of electron transport system (ETS) complexes and ATP-synthase in the cortex and striatum of symptomatic R6/2 mice. Our findings reveal a brain-region-specific differential expression of both nuclear and mitochondrial-encoded ETS components, indicating defects of transcription, translation and/or mitochondrial import of mitochondrial ETS components in R6/2 mouse brains.


2018 ◽  
Author(s):  
Mutwakil Abdulla ◽  
Amit Jathoul ◽  
Ngoc-Nga Vinh ◽  
Ying Zhu ◽  
David Williams ◽  
...  

2019 ◽  
Vol 29 (2) ◽  
pp. 216-227
Author(s):  
Sheridan L Roberts ◽  
Tracey Evans ◽  
Yi Yang ◽  
Yuhua Fu ◽  
Robert W Button ◽  
...  

Abstract Huntington’s disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine tract in the huntingtin (HTT) protein. Mutant HTT (mHTT) toxicity is caused by its aggregation/oligomerization. The striatum is the most vulnerable region, although all brain regions undergo neuronal degeneration in the disease. Here we show that the levels of Bim, a BH3-only protein, are significantly increased in HD human post-mortem and HD mouse striata, correlating with neuronal death. Bim reduction ameliorates mHTT neurotoxicity in HD cells. In the HD mouse model, heterozygous Bim knockout significantly mitigates mHTT accumulation and neuronal death, ameliorating disease-associated phenotypes and lifespan. Therefore, Bim could contribute to the progression of HD.


2019 ◽  
Vol 8 (2) ◽  
pp. 161-169 ◽  
Author(s):  
Anna C. Pfalzer ◽  
Phillip A. Wages ◽  
Ned A. Porter ◽  
Aaron B. Bowman

2008 ◽  
Vol 275 (1645) ◽  
pp. 1865-1874 ◽  
Author(s):  
Kate Littin ◽  
Abraham Acevedo ◽  
William Browne ◽  
Joanne Edgar ◽  
Mike Mendl ◽  
...  

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