Visual pathway neurodegeneration winged by mitochondrial dysfunction

Petzold, Axel; Nijland, Philip G.; Balk, Lisanne J.; Amorini, Angela Maria; Lazzarino, Giacomo; Wattjes, Mike P.; Gasperini, Claudio; Valk, Paul van der; Tavazzi, Barbara; Lazzarino, Giuseppe; Horssen, Jack van

doi:10.1002/acn3.157

Cited by 14 publications

(8 citation statements)

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“…Simons et al suggest that the greater variability of degeneration in the CNS depends on the stoichiometry of the axon-oligodendrocyte relationship which varies in different parts of the brain. There is prospective data to suggest that such a relationship can be tested in vivo by combining body fluid biomarkers with MRI and retinal OCT (Petzold et al 2015). Particularly neurofilament proteins, specific biomarkers for neurodegeneration, have advanced the field (Khalil et al 2018;Petzold 2005).…”

Section: Discussionmentioning

confidence: 99%

Patterns of retrograde axonal degeneration in the visual system

Vries-Knoppert

Baaijen

Petzold

2019

Brain

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Conclusive evidence for existence of acquired retrograde axonal degeneration that is truly trans-synaptic (RTD) has not yet been provided for the human visual system. Convincing data rely on experimental data of lesions to the posterior visual pathways. This study aimed to overcome the limitations of previous human studies, namely pathology to the anterior visual pathways and neurodegenerative co-morbidity. In this prospective, longitudinal cohort retinal optical coherence tomography scans were acquired before and after elective partial temporal lobe resection in 25 patients for intractable epilepsy. Newly developed region of interest-specific, retinotopic areas substantially improved on conventional reported early treatment diabetic retinopathy study (ETDRS) grid-based optical coherence tomography data. Significant inner retinal layer atrophy separated patients with normal visual fields from those who developed a visual field defect. Acquired RTD affected the retinal nerve fibre layer, ganglion cell and inner plexiform layer and stopped at the level of the inner nuclear layer. There were significant correlations between the resected brain tissue volume and the ganglion cell layer region of interest (R = −0.78, P < 0.0001) and ganglion cell inner plexiform layer region of interest (R = −0.65, P = 0.0007). In one patient, damage to the anterior visual pathway resulted in occurrence of microcystic macular oedema as recognized from experimental data. In the remaining 24 patients with true RTD, atrophy rates in the first 3 months were strongly correlated with time from surgery for the ganglion cell layer region of interest (R = −0.74, P < 0.0001) and the ganglion cell inner plexiform layer region of interest (R = −0.51, P < 0.0001). The different time course of atrophy rates observed relate to brain tissue volume resection and suggest that three distinct patterns of retrograde axonal degeneration exist: (i) direct retrograde axonal degeneration; (ii) rapid and self-terminating RTD; and (iii) prolonged RTD representing a ‘penumbra’, which slowly succumbs to molecularly governed spatial cellular stoichiometric relationships. We speculate that the latter could be a promising target for neuroprotection.

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Section: Discussionmentioning

confidence: 99%

Patterns of retrograde axonal degeneration in the visual system

Vries-Knoppert

Baaijen

Petzold

2019

Brain

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“…Furthermore, imaging studies in MS patients indicate that both glucose and lactate metabolism is increased in active MS lesions [ 39 , 41 , 50 ]. Lactate levels were also found to be increased in the CSF and serum of MS patients and to correlate with disease progression [ 1 , 35 ]. These studies suggest that the changes in GME expression levels we found are associated with alterations in the glycolytic and TCA cycle fluxes.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of glucose-metabolizing enzymes in multiple sclerosis lesions

Nijland

Molenaar

Pol

et al. 2015

acta neuropathol commun

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IntroductionDemyelinated axons in multiple sclerosis (MS) lesions have an increased energy demand in order to maintain conduction. However, oxidative stress-induced mitochondrial dysfunction likely alters glucose metabolism and consequently impairs neuronal function in MS. Imaging and pathological studies indicate that glucose metabolism is altered in MS, although the underlying mechanisms and its role in neurodegeneration remain elusive. We investigated expression patterns of key enzymes involved in glycolysis, tricarboxylic acid (TCA) cycle and lactate metabolism in well-characterized MS tissue to establish which regulators of glucose metabolism are involved in MS and to identify underlying mechanisms.ResultsExpression levels of glycolytic enzymes were increased in active and inactive MS lesions, whereas expression levels of enzymes involved in the TCA cycle were upregulated in active MS lesions, but not in inactive MS lesions. We observed reduced expression and production capacity of mitochondrial α-ketoglutarate dehydrogenase (αKGDH) in demyelinated axons, which correlated with signs of axonal dysfunction. In inactive lesions, increased expression of lactate-producing enzymes was observed in astrocytes, whereas lactate-catabolising enzymes were mainly detected in axons. Our results demonstrate that the expression of various enzymes involved in glucose metabolism is increased in both astrocytes and axons in active MS lesions. In inactive MS lesions, we provide evidence that astrocytes undergo a glycolytic shift resulting in enhanced astrocyte-axon lactate shuttling, which may be pivotal for the survival of demyelinated axons.ConclusionIn conclusion, we show that key enzymes involved in energy metabolism are differentially expressed in active and inactive MS lesions. Our findings imply that, in addition to reduced oxidative phosphorylation activity, other bioenergetic pathways are affected as well, which may contribute to ongoing axonal degeneration in MS.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0261-8) contains supplementary material, which is available to authorized users.

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“…In the normal healthy state, the generation of ROS occurs in a controlled manner, with mitochondria as the main intracellular source of ROS in the form of superoxide anions through the electron transport chain [2]. Increased ROS production occurs under high-stress conditions or in various disease states such as acute [3,4] and chronic neurodegenerations [5], stroke [6], ischemia [7] and male infertility [8]. These pathologic conditions are characterized by malfunctioning mitochondria, which are unable to correctly catalyze the tetravalent reduction of molecular oxygen to water in the electron transport chain, leading to increased ROS generation from aerobic respiration.…”

Section: Introductionmentioning

confidence: 99%

Water- and Fat-Soluble Antioxidants in Human Seminal Plasma and Serum of Fertile Males

Lazzarino

Listorti²,

Bilotta³

et al. 2019

Antioxidants

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Reactive oxygen species (ROS) are physiologically involved in functions like sperm maturation, capacitation and acrosome reaction, but their excess is involved in male infertility. Antioxidants in seminal plasma (SP) are an important factor balancing physiologic and harmful ROS activities. In this study, we determined and compared the full profiles of the water- and fat-soluble antioxidants in SP and serum of 15 healthy fertile subjects (ranging between the ages of 35 and 42 years). Ejaculates were obtained after 2–5 days of sexual abstinence. After liquefaction and withdrawal of an aliquot for the sperm count, samples were centrifuged to obtain SP. Thirty min after semen donation, a venous blood sample was collected from each subject. Donors with lower SP concentrations of ascorbic acid (n = 5) or α-tocopherol (n = 5) received a 4 week oral administration of either vitamin C (100 mg/day) or vitamin E (30 mg/day). They were then re-assayed to determine the SP and serum levels of ascorbic acid and α-tocopherol. SP and serum samples were properly processed and analyzed by HPLC methods suitable to determine water (ascorbic acid, glutathione (GSH) and uric acid) and fat-soluble (all-trans-retinoic acid, all-trans-retinol, α-tocopherol, carotenoids and coenzyme Q10) antioxidants. Data demonstrate that only ascorbic acid is higher in SP than in serum (SP/serum ratio = 4.97 ± 0.88). The other water-soluble antioxidants are equally distributed in the two fluids (GSH SP/serum ratio = 1.14 ± 0.34; uric acid SP/serum ratio = 0.82 ± 0.12). All fat-soluble antioxidants are about 10 times less concentrated in SP than in serum. In donors treated with vitamin C or vitamin E, ascorbic acid and α-tocopherol significantly increased in both fluids. However, the SP/serum ratio of ascorbic acid was 4.15 ± 0.45 before and 3.27 ± 0.39 after treatment, whilst those of α-tocopherol were 0.11 ± 0.03 before and 0.10 ± 0.02 after treatment. The results of this study, by showing the peculiar composition in water- and fat-soluble antioxidants SP, indicate that it is likely that still-unknown mechanisms allow ascorbic acid accumulation in SP against a concentration gradient. SP mainly relies its defenses on water- rather than fat-soluble antioxidants and on the mechanisms ensuring their transfer from serum.

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Visual pathway neurodegeneration winged by mitochondrial dysfunction

Cited by 14 publications

References 50 publications

Patterns of retrograde axonal degeneration in the visual system

Patterns of retrograde axonal degeneration in the visual system

Differential expression of glucose-metabolizing enzymes in multiple sclerosis lesions

Water- and Fat-Soluble Antioxidants in Human Seminal Plasma and Serum of Fertile Males

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