Biology subjects

Moldovan, M.

Publications and source records attributed to Moldovan, M..

5 recordsLinked to original sources

bioRxiv2022

Homeostatic changes maintain the gain control of spinal motoneurones across the lifetime of C57BL/6J mice

Age-related changes in the excitability of spinal motoneurone have been observed in mouse models of neurodegenerative diseases affecting these neurones. How the excitability of spinal motoneurones change with healthy ageing in mice and how this compares with that seen in neurodegenerative diseases is unknown. Therefore, we performed in vivo intracellular recording from identified spinal motoneurones in C57BL/6 mice at three different ages (100, 300-400 and 600-750 days old). Behavioral tests confirmed a linear reduction in motor function across these ages (using the rotorod test). Significant differences were observed with respect to the features of individual somatic action potential with ageing including a decreased rate of rise and fall in aged mice. Surprisingly, the rate of rise of the action potential at the initial segment was altered in middle aged mice. Immunohistochemical labelling of the axon initial segment of the motoneurones confirmed structural changes occurring at middle age (decreased length and diameter) but returning to the earlier parameters in aged mice. To explore the effects on repetitive firing, this was tested across the age groups which showed surprising little difference as the mice aged, with a similar rheobase and I-f gain across all age groups (with the exception of a lower voltage threshold for action potential initiation in middle-aged mice). However, amplitudes of the after-hyperpolarization and the input resistance were both found to be significantly altered with age. We conclude that there are changes occurring in the intrinsic properties of spinal motoneurones that control their excitability over the lifetime of mice, although these do not develop in a linear fashion from young to old. We propose that these changes are homeostatic in nature and are able to compensate for one another to maintain a constant gain control across the lifetime.

neuroscience↗

bioRxiv2020

Lipidomic profiling of clinical prostate cancer reveals targetable alterations in lipid composition

Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Herein, we used quantitative mass spectrometry to define the "lipidome" in prostate tumors with matched benign tissues (n=21), independent tissues (n=47), and primary prostate explants cultured with a clinical AR antagonist, enzalutamide (n=43). Significant differences in lipid composition were detected and spatially visualized in tumors compared to matched benign samples. Notably, tumors featured higher proportions of monounsaturated lipids overall and elongated fatty acid chains in phosphatidylinositol and phosphatidylserine lipids. Significant associations between lipid profile and malignancy were validated in unmatched samples, and PL composition was characteristically altered in patient tissues that responded to AR inhibition. Importantly, targeting of altered tumor-related lipid features, via inhibition of acetyl CoA carboxylase 1, significantly reduced cellular proliferation in tissue explants (n=13). This first characterization of the prostate cancer lipidome in clinical tissues revealed enhanced fatty acid synthesis, elongation and desaturation as tumor-defining features, with potential for therapeutic targeting.

cancer biology↗

bioRxiv2020

A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth

Alterations to androgen receptor (AR) signalling and cellular metabolism are hallmarks of prostate cancer. This study uncovers a novel link between AR and the pentose phosphate pathway (PPP) through 6-phosphogluoconate dehydrogenase (6PGD), an androgen-regulated gene that is upregulated in prostate cancer. Knockdown of 6PGD impairs growth and elicits death of prostate cancer cells, at least in part due to oxidative stress. Targeting 6PGD using 2 specific inhibitors, physcion and S3, was efficacious in multiple models of prostate cancer, including aggressive castration-resistant models. Importantly, S3 also suppressed proliferation of clinical patient-derived explants (PDEs). Mechanistically, 6PGD decreased expression and activity of AR in cell lines and PDEs, revealing a novel positive feedback loop between these factors. The enhanced efficacy of co-targeting AR and 6PGD further supported the biological relevance of this feedback. This work provides insight into the dysregulated metabolism of prostate cancer and supports investigation of co-targeting AR and the PPP.

cancer biology↗

bioRxiv2020

Increased axon initial segment length results in increased Na+ currents in spinal motoneurones at symptom onset in the G127X SOD1 mouse model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis is a neurodegenerative disease preferentially affecting motoneurones. Transgenic mouse models have been used to investigate the role of abnormal motoneurone excitability in this disease. Whilst an increased excitability has repeatedly been demonstrated in vitro in neonatal and embryonic preparations from SOD1 mouse models, the results from the only studies to record in vivo from spinal motoneurones in adult SOD1 models have produced conflicting findings. Deficits in repetitive firing have been reported in G93A SOD1 mice but not in presymptomatic G127X SOD1 mice despite shorter motoneurone axon initial segments (AISs) in these mice. These discrepancies may be due to the earlier disease onset and prolonged disease progression in G93A SOD1 mice with recordings potentially performed at a later sub-clinical stage of the disease in this mouse. To test this, and to explore how the evolution of excitability changes with symptom onset we performed in vivo intracellular recording and AIS labelling in G127X SOD1 mice immediately after symptom onset. No reductions in repetitive firing were observed showing that this is not a common feature across all ALS models. Immunohistochemistry for the Na+ channel Nav1.6 showed that motoneurone AISs increase in length in G127X SOD1 mice at symptom onset. Consistent with this, the rate of rise of AIS components of antidromic action potentials were significantly faster confirming that this increase in length represents an increase in AIS Na+ channels occurring at symptom onset in this model. HighightsO_LIIn vivo electrophysiological recordings were made in symptomatic G127X SOD1 mice. C_LIO_LIThere were no deficits in repetitive firing in motoneurones in G127X mice. C_LIO_LIIncreased persistent inward currents were still present in the symptomatic mice. C_LIO_LIResults suggest increases in Na+ currents at axon initial segments (AISs). C_LIO_LIImmunohistochemistry showed that motoneurone AISs were longer and thinner. C_LI

neuroscience↗

bioRxiv2019

DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis

Fatty acid {beta}-oxidation (FAO) is the main bioenergetic pathway in prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, which encodes the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown in PCa cells selectively inhibited {beta}-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation in vivo. Mechanistically, targeting of DECR1 caused cellular accumulation of linoleic acid, enhanced mitochondrial oxidative stress and lipid peroxidation, and ferroptosis. These findings implicate PUFA oxidation via DECR1 as a previously unexplored facet of FAO that promotes survival of PCa cells.

cancer biology↗