Regional changes in CNS and retinal glycerophospholipid profiles with age: a molecular blueprint

Hopiavuori, Blake R.; Agbaga, Martin-Paul; Brush, Richard S.; Sullivan, Michael T.; Sonntag, William E.; Anderson, Robert E.

doi:10.1194/jlr.m070714

Cited by 32 publications

(32 citation statements)

References 120 publications

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“…The methods have been described previously 35 , 36 . Briefly, ROSs were diluted 1 : 40 with 2-propanol/methanol/chloroform (4 : 2 : 1 v/v/v) containing 20 mM ammonium formate and 1.00 µM PC 14 : 0/14 : 0, 1.00 µM PE 14 : 0/14 : 0, and 0.33 µM PS 14 : 0/14 : 0 as internal standards.…”

Section: Methodsmentioning

confidence: 99%

Pyruvate kinase M2 regulates photoreceptor structure, function, and viability

et al. 2018

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Pyruvate kinase M2 (PKM2) is a glycolytic enzyme that is expressed in cancer cells. Its role in tumor metabolism is not definitively established, but investigators have suggested that regulation of PKM2 activity can cause accumulation of glycolytic intermediates and increase flux through the pentose phosphate pathway. Recent evidence suggests that PKM2 also may have non-metabolic functions, including as a transcriptional co-activator in gene regulation. We reported previously that PKM2 is abundant in photoreceptor cells in mouse retinas. In the present study, we conditionally deleted PKM2 (rod-cre PKM2-KO) in rod photoreceptors and found that the absence of PKM2 causes increased expression of PKM1 in rods. Analysis of metabolic flux from U-13C glucose shows that rod-cre PKM2-KO retinas accumulate glycolytic intermediates, consistent with an overall reduction in the amount of pyruvate kinase activity. Rod-cre PKM2-KO mice also have an increased NADPH availability could favor lipid synthesis, but we found no difference in phospholipid synthesis between rod-cre PKM2 KO and PKM2-positive controls. As rod-cre PKM2-KO mice aged, we observed a significant loss of rod function, reduced thickness of the photoreceptor outer segment layer, and reduced expression of photoreceptor proteins, including PDE6β. The rod-cre PKM2-KO retinas showed greater TUNEL staining than wild-type retinas, indicating a slow retinal degeneration. In vitro analysis showed that PKM2 can regulate transcriptional activity from the PDE6β promoter in vitro. Our findings indicate that both the metabolic and transcriptional regulatory functions of PKM2 may contribute to photoreceptor structure, function, and viability.

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Section: Methodsmentioning

confidence: 99%

Pyruvate kinase M2 regulates photoreceptor structure, function, and viability

et al. 2018

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“…Data is represented as relative mole percent of each FA species. Additionally, the retinal phospholipid composition was analyzed by methods described previously [ 21 , 48 ]. Briefly, retinas were homogenized in methanol and diluted 1:40 with 2-propanol/methanol/chloroform (4:2:1 v/v/v) containing 20 mM ammonium formate and 1.00 μM PC 14:0/14:0, 1.00 μM phosphatidylethanolamine (PE) 14:0/14:0 and 0.33 μM phosphatidylserine (PS) 14:0/14:0 as internal standards.…”

Section: Methodsmentioning

confidence: 99%

“…ELOVL4 is primarily expressed in skin, testis, retina and brain where it elongates saturated (skin and brain [ 19 – 21 ]) and polyunsaturated (retina and testis [ 22 – 24 ]) FA. Very long chain saturated fatty acids (VLC-SFAs) and very long-chain poly unsaturated fatty acids (VLC-PUFAs) do not exist as free FA, but rather have their carboxyl terminus linked to a headgroup like e.g.…”

Section: Introductionmentioning

confidence: 99%

Elovl4 5-bp deletion does not accelerate cone photoreceptor degeneration in an all-cone mouse

et al. 2018

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Mutations in the elongation of very long chain fatty acid 4 (ELOVL4) gene cause Stargardt macular dystrophy 3 (STGD3), a rare, juvenile-onset, autosomal dominant form of macular degeneration. Although several mouse models have already been generated to investigate the link between the three identified disease-causing mutations in the ELOVL4 gene, none of these models recapitulates the early-onset cone photoreceptor cell death observed in the macula of STGD3 patients. To address this specifically, we investigated the effect of mutant ELOVL4 in a mouse model with an all-cone retina. Hence, we bred mice carrying the heterozygously mutated Elovl4 gene on the R91W;Nrl-/- all-cone background and analyzed the retinal lipid composition, morphology, and function over the course of 1 year. We observed a reduction of total phosphatidylcholine-containing very long chain-polyunsaturated fatty acids (PC-VLC-PUFAs) by 39% in the R91W;Nrl-/-;Elovl4 mice already at 6 weeks of age with a pronounced decline of the longest forms of PC-VLC-PUFAs. Total levels of shorter-chain fatty acids (< C26) remained unaffected. However, this reduction in PC-VLC-PUFA content in the all-cone retina had no impact on morphology or function and did not accelerate retinal degeneration in the R91W;Nrl-/-;Elovl4 mice. Taken together, mutations in the ELOVL4 gene lead to cone degeneration in humans, whereas mouse models expressing the mutant Elovl4 show predominant rod degeneration. The lack of a phenotype in the all-cone retina expressing the mutant form of the protein supports the view that aberrant function of ELOVL4 is especially detrimental for rods in mice and suggests a more subtle role of VLC-PUFAs for cone maintenance and survival.

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“…DHA is also used as a signal transduction molecule, which protects from neuronal damages in oxidative injuries to the retina (Mukherjee et al, ). Phosphatidyletanolamine (PE) and PS work as storage for DHA (LeKim & Betzing, ) and their 40:06; PS (18:0/22:6n3) and PE (18:0/22:6n3) are major molecules in retinal tissue (Hopiavuori et al, ). Our results revealed that expression of several species of PE that include DHA are upregulated in whole TONI retinal tissue (Figure , e, g, h), whereas PE species with mono‐ or di‐unsaturated fatty acids did not change (Figure , a, b, c).…”

Section: Discussionmentioning

confidence: 99%

“…It is known that retinal tissue has highly unique lipids that play critical roles in retinal function (Fliesler & Anderson, ) and are related to diseases such as age‐related macular degeneration (Liu, Chang, Lin, Shen, & Bernstein, ). The phospholipids in retinal tissue have been well characterized by gas chromatography–mass spectrometry (Aveldaño & Bazán, ; Aveldaño & Sprecher, ), electrospray mass spectrometry (Acar et al, ; Berdeaux et al, ; Ford et al, ), and tandem mass spectrometry (Hopiavuori et al, ). The retinal tissue is highly enriched in polyunsaturated fatty acids (PUFAs), with docosahexaenoic acid (DHA) (22:6) (22 carbons with 6 double bonds) accounting for approximately 50% of the fatty acids in the photoreceptors (Fliesler & Anderson, ).…”

Section: Introductionmentioning

confidence: 99%

Change in phospholipid species of retinal layer in traumatic optic neuropathy model

Hirahara

Wakabayashi

Koike

et al. 2019

J of Neuroscience Research

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Injured optic nerves induce death in almost all retinal ganglion cells (RGC) and cause a loss of axons. To date, we have studied injured RGC axon regeneration by using a traumatic optic nerve injury (TONI) rodent model, and we revealed that axonal regeneration is induced by the graft of an autologous peripheral nerve. The efficient approach to the regeneration of axons thus needs an environmental adjustment of RGC. However, the RGC environment induced by TONI remains unknown. Here, we analyzed female and male C57BL/6 mouse retinal tissue alterations in detail after TONI and focused on the major phospholipid species that are enriched in the whole retina. Reactive astrocyte accumulation, glia scar formation, and demyelination were observed in the injured optic nerve area, while RGC cell death, astrocyte accumulation, and Glial fibrillary acidic protein (GFAP) positive Müller cell increases were detected in the retinal layer. Furthermore, phosphatidylinositol (PI) 18:0/20:4 was localized to three nuclear layer structures: the ganglion cell layer (GCL), the inner nuclear layer (INL), and the outer nuclear layer (ONL) in control retina; however, the localization of 18:0/20:4 PI in TONI was disturbed. Meanwhile, phosphatidylserine (PS) 18:0/22:6showed that the expression was specifically in the inner plexiform layer (IPL) with similar signal intensity in both cases. Other PS species and phosphatidylethanolamine (PE) were differentially localized in the retinal layer; however, the expressions of PE including docosahexaenoic acid (DHA) were affected by TONI. These results suggest that not only GCL but also other retinal layers were influenced by TONI.

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Regional changes in CNS and retinal glycerophospholipid profiles with age: a molecular blueprint

Cited by 32 publications

References 120 publications

Pyruvate kinase M2 regulates photoreceptor structure, function, and viability

Pyruvate kinase M2 regulates photoreceptor structure, function, and viability

Elovl4 5-bp deletion does not accelerate cone photoreceptor degeneration in an all-cone mouse

Change in phospholipid species of retinal layer in traumatic optic neuropathy model

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