ReviewRole of mitochondrial dysfunction in the pathogenesis of Huntington's disease
Introduction
Huntington disease (HD) is a neurodegenerative disease that is caused by the pathological elongation of the CAG repeats in exon one of the huntingtin protein gene [27], [30], [81], although the resulting pathogenic processes have not been fully elucidated [27]. However transcriptional deregulation [3], [15] and mitochondrial dysfunction [49], [56], [63] have been strongly implicated in the pathogenesis of HD. In this review, we explore the role of mitochondrial dysfunction in the pathogenesis of HD and the contribution of transcriptional dysregulation, and discuss possible therapeutic interventions based on these findings.
Section snippets
Clinical and pathological aspects
HD is an autosomal dominant neurodegenerative disorder, which inevitably leads to the death of affected individuals. The clinical features of HD classically involve progressive motor dysfunction and psychiatric disturbances with gradual dementia [32], [51]. The clinical progression of HD is paralleled by a selective pattern of neuronal degeneration initially in the striatum and at later stages of the disease in the cerebral cortex [81]. In the striatum the neuronal loss is associated with
Mitochondrial permeability transition pore (mPTP) opening inhibitors
It has been suggested that the neuroprotective properties of CsA are due in part to its ability to prevent mPTP opening in response to high levels of calcium or oxidative stress [52], [58]. Exposure to high levels of calcium or oxidative stress results in the mPTP opening of the inner mitochondrial membrane, causing disruption of Δψm, and swelling of mitochondria [40], [47], [58]. In vitro CsA attenuates apoptosis induced by the mitochondrial complex 1 inhibitor rotenone [68], and also the
Conclusions and working hypothesis
Fig. 1 illustrates our hypothesis of how mutant huntingtin may compromise mitochondrial function and possible therapeutic targets. We hypothesize that the mutant huntingtin expression induced inhibition of CREB/TAF4 as well as CBP results in a downregulation and decrease in the activity of PGC-1α, and this subsequently results in a decrease in the activity of transcription factors such as PPARγ and hence a decrease in the expression of mitochondrial genes which results in compromised
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Modeling Huntington's disease: An insight on in-vitro and in-vivo models
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2023, NeuropeptidesLongitudinal spatial mapping of lipid metabolites reveals pre-symptomatic changes in the hippocampi of Huntington's disease transgenic mice
2023, Neurobiology of DiseaseCitation Excerpt :Additionally, there was a striking loss of GM1, PS, PI lipid classes that have been shown to contribute to LTP and modulation of NMDA receptors, mechanisms that underlie hippocampal synaptic plasticity and associated learning and memory (Borghese, and Go'mez RA, Rami'rez OA., 1993; Bradley et al., 2017; Nolan et al., 2004; Fujii et al., 2002). Hence the reduced abundances of PE, PS, PI and GM1 in the CA1 subfield of 12- and 16-week-old HD mice may contribute to mechanisms implicated in onset of HD symptoms, including deficits in BDNF signaling (Zuccato et al., 2005), aberrant synaptic plasticity (Murphy et al., 2000b; Smith-Dijak et al., 2019) and mitochondrial dysfunction (Kim et al., 2010; Quintanilla and Johnson, 2009). In particular, the reduced abundance of the neuronal-specific DHA-containing PS (44:12) (Guo et al., 2007) in the CA1 subfield of 12-week-old HD mice may contribute to the loss of cognitive function and long-term memory in HD (Giralt et al., 2012a; Ransome et al., 2012b; Giralt et al., 2012b), as this lipid is known to play a significant role in improving memory and cognitive abilities in elderly subjects with mild cognitive impairments (Vakhapova et al., 2014; Yurko-Mauro et al., 2010).
Deciphering the key mechanisms leading to alteration of lipid metabolism in Drosophila model of Huntington's disease
2021, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :Defects in energy metabolism has also been evidenced in skeletal muscle tissue of HD R6/2 mice exhibiting increased susceptibility of mitochondria to calcium stress ultimately leading to muscular atrophy [63]. Transcriptional deregulation involving HSF1, p53 and PGC-1α; defects in mitochondrial dynamics (fission and fusion) leading to mitophagy; impaired handling of mitochondrial calcium and decreased activity of complex II, III and IV of the ETC (electron transport chain) are the major putative mechanisms leading to mitochondrial dysfunction in HD (reviewed by [26,64–66]). As assessing the fate of mitochondrial function became primarily important in order to decipher the cellular mechanisms leading to cell death, we stained the fat body with Mitotracker red CMX-ROS dye which specifically labels actively respiring mitochondria.