Uncoupling proteins as a therapeutic target for the development of new era drugs against neurodegenerative disorder

Kumar, Rahul; Amruthanjali, T; Singothu, Siva; Singh, Shashi Bala; Bhandari, Vasundhra

doi:10.1016/j.biopha.2022.112656

Cited by 30 publications

(28 citation statements)

References 108 publications

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“…Notably, this function is important for mitochondrial calcium homeostasis, and deficient m-AAA function leads to constitutive calcium uniporter activity and increased mitochondrial calcium uptake (Patron et al, 2018). Ucp2 can also regulate mitochondrial levels (Koshenov et al, 2020) in a manner thought to promote homeostasis (Kumar et al, 2022). In contrast, Gimap5 , which was upregulated in bLRs, enhances mitochondrial calcium intake (X. L. Chen et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, down-regulation of Spg7, Afg3l1 , and Cav1 in bLR-like animals might increase risk for cell loss or inflammation, especially after periods of intense neuronal activity, such as occurs during a stress response (Zalachoras et al, 2020). Likewise, Ucp2 is considered neuroprotective, and decreased Ucp2 , such as seen in bLRs, is linked to inflammation and neurodegeneration (Hass & Barnstable, 2016; Kumar et al, 2022), whether through altered mitochondrial calcium and oxidative phosphorylation, or other mechanisms discussed below.…”

Section: Discussionmentioning

confidence: 99%

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Bioenergetic-Related Gene Expression in the Hippocampus Predicts Internalizing vs. Externalizing Behavior in a F₂Cross of Selectively-Bred Rats

Hebda-Bauer

Hagenauer

Blandino

et al. 2022

Preprint

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In humans, differences in temperament are highly predictive of classes of psychopathology classified as externalizing versus internalizing disorders. To better understand the genetic and neural causes of temperamental differences, we have selectively bred two lines of rats based on their exploration of a novel environment. The bred High Responder (bHR) and bred Low Responder (bLR) rats show contrasting heritable behaviors that map onto human temperamental differences and are associated with two paths to drug abuse—sensation seeking and reactivity to psychosocial stress. To elucidate the genes that underlie the divergent behavior of bHR/bLR rats, we created a bHRxbLR F0-F1-F2 cross and performed behavioral testing, transcriptional profiling, and genetic sequencing. We used RNA-Seq to characterize hippocampal tissue in F0s (n=24, n=6 per phenotype /sex) and F2s (n=250, n=125 per sex) to identify differentially expressed genes related to bHR/bLR lineage and phenotypical behaviors: locomotor response to novelty, anxiety, and Pavlovian Conditioned Approach (PavCA).We found that bHR/bLR phenotypical behaviors remained correlated in the F2s, implying a shared genetic basis. We also found robust differences in hippocampal transcriptional profiles associated with bHR/bLR lineage in the F0s which surpassed the differences associated with sex. These distinct expression profiles were predictive of gene expression patterns associated with F2 bHR/bLR behavior. We then prioritized bHR/bLR differentially expressed genes identified in our current and previous studies as candidates for mediating bHR/bLR phenotypical behaviors in F2s. Seventeen genes were differentially expressed in association with locomotor response to novelty, many of which also had nominal relationships with PavCA behavior. Seven of these genes were located near (+/−1MB) quantitative trait loci for bHR/bLR phenotypical behavior identified in our previous exome sequencing or genome wide association studies: AABR07071904, Ucp2, Ttc30a1, Fzd6, Spg7, Vps9d1, and Afg3l1. We also identified convergence between our model and other genetic rat models targeting internalizing behaviors, with 26 hippocampal genes showing shared patterns of differential expression, including Tmem144 and Mfge8. Our findings provide strong candidates for elucidating genetic and neurobiological factors that may shape differences in temperament and modulate vulnerability to psychiatric and addictive disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Bioenergetic-Related Gene Expression in the Hippocampus Predicts Internalizing vs. Externalizing Behavior in a F₂Cross of Selectively-Bred Rats

Hebda-Bauer

Hagenauer

Blandino

et al. 2022

Preprint

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“…UCP2, in addition to its uncoupling role, is known to regulate lipid metabolism, generation of ROS, and inflammation. It plays important roles in the brain, regulating energy balance, inflammation, membrane potential, and cell death, and its dysregulation in PD results in increased neuronal cell death [62]. Some studies have shown that UCP2 is elevated in PD brains [63].…”

Section: Discussionmentioning

confidence: 99%

Dysregulated Gene Expression in Lymphoblasts from Parkinson’s Disease

et al. 2022

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Parkinson’s disease is the second largest neurodegenerative disease worldwide and is caused by a combination of genetics and environment. It is characterized by the death of neurons in the substantia nigra of the brain but is not solely a disease of the brain, as it affects multiple tissues and organs. Studying Parkinson’s disease in accessible tissues such as skin and blood has increased our understanding of the disease’s pathogenesis. Here, we used lymphoblast cell lines generated from Parkinson’s disease patient and healthy age- and sex-matched control groups and obtained their whole-cell transcriptomes and proteomes. Our analysis revealed, in both the transcriptomes and the proteomes of PD cells, a global downregulation of genes involved in protein synthesis, as well as the upregulation of immune processes and sphingolipid metabolism. In contrast, we discovered an uncoupling of mRNA and protein expression in processes associated with mitochondrial respiration in the form of a general downregulation in associated transcripts and an upregulation in proteins. Complex V was different to the other oxidative phosphorylation complexes in that the levels of its associated transcripts were also lower, but the levels of their encoded polypeptides were not elevated. This may suggest that further layers of regulation specific to Complex V are in play.

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“…However, in the present study, UCP2 overexpression resulted in mitochondrial ROS production and exacerbated oxidative damage. UCP2 has a dual role in regulating the ATP synthase and modulating redox homeostasis (Krauss et al 2005 ; Kumar et al 2022 ). Upregulation of UCP2 within a certain range, or compensatory increase, is protective and causes mild uncoupling, thus reducing ROS production and mitigating oxidative damage; whereby UCP2 overexpression causes excessive mitochondrial uncoupling, which is harmful.…”

Section: Discussionmentioning

confidence: 99%

AAV-ie-mediated UCP2 overexpression accelerates inner hair cell loss during aging in vivo

Zhao

Zhan

Chen

et al. 2022

Mol Med

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Background Uncoupling protein 2 (UCP2), activated by excessive reactive oxygen species (ROS) in vivo, has the dual effect of reducing ROS to protect against oxidative stress and reducing ATP production to regulate cellular metabolism. Both the UCP2 and ROS are increased in cochleae in age-related hearing loss (ARHL). However, the role of UCP2 in sensory hair cells in ARHL remains unclear. Methods Male C57BL/6 J mice were randomly assigned to an 8-week-old group (Group 1), a 16-week-old group (Group 2), a 16-week-old + adeno-associated virus-inner ear (AAV-ie) group (Group 3), and a 16-week-old + AAV-ie-UCP2 group (Group 4). Mice aged 8 weeks were administrated with AAV-ie-GFP or AAV-ie-UCP2 via posterior semicircular canal injection. Eight weeks after this viral intervention, hearing thresholds and wave-I amplitudes were tested by auditory brainstem response (ABR). Subsequently, the cochlear basilar membrane was dissected for investigation. The number of hair cells and inner hair cell (IHC) synapses, the level of ROS, and the expression of AMP-activated protein kinase α (AMPKα), were assessed by immunofluorescence staining. In addition, mitochondrial function was determined, and the expression of AMPKα and UCP2 proteins was further evaluated using western blotting. Results Mice with early-onset ARHL exhibited enhanced oxidative stress and loss of outer hair cells and IHC synapses, while UCP2 overexpression aggravated hearing loss and cochlear pathophysiological changes in mice. UCP2 overexpression resulted in a notable decrease in the number of IHCs and IHC synapses, caused ATP depletion and excessive ROS generation, increased AMPKα protein levels, and promoted IHC apoptosis, especially in the apical and middle turns of the cochlea. Conclusion Collectively, our data suggest that UCP2 overexpression may cause mitochondrial dysfunction via energy metabolism, which activates mitochondrion-dependent cellular apoptosis and leads to IHC loss, ultimately exacerbating ARHL.

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Uncoupling proteins as a therapeutic target for the development of new era drugs against neurodegenerative disorder

Cited by 30 publications

References 108 publications

Bioenergetic-Related Gene Expression in the Hippocampus Predicts Internalizing vs. Externalizing Behavior in a F₂Cross of Selectively-Bred Rats

Bioenergetic-Related Gene Expression in the Hippocampus Predicts Internalizing vs. Externalizing Behavior in a F₂Cross of Selectively-Bred Rats

Dysregulated Gene Expression in Lymphoblasts from Parkinson’s Disease

AAV-ie-mediated UCP2 overexpression accelerates inner hair cell loss during aging in vivo

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Uncoupling proteins as a therapeutic target for the development of new era drugs against neurodegenerative disorder

Cited by 30 publications

References 108 publications

Bioenergetic-Related Gene Expression in the Hippocampus Predicts Internalizing vs. Externalizing Behavior in a F2Cross of Selectively-Bred Rats

Bioenergetic-Related Gene Expression in the Hippocampus Predicts Internalizing vs. Externalizing Behavior in a F2Cross of Selectively-Bred Rats

Dysregulated Gene Expression in Lymphoblasts from Parkinson’s Disease

AAV-ie-mediated UCP2 overexpression accelerates inner hair cell loss during aging in vivo

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Bioenergetic-Related Gene Expression in the Hippocampus Predicts Internalizing vs. Externalizing Behavior in a F₂Cross of Selectively-Bred Rats

Bioenergetic-Related Gene Expression in the Hippocampus Predicts Internalizing vs. Externalizing Behavior in a F₂Cross of Selectively-Bred Rats