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Expression profiling of the ubiquitin conjugating enzyme UbcM2 in murine brain reveals modest age-dependent decreases in specific neurons.

Larabee CM, Georgescu C, Wren JD, Plafker SM - BMC Neurosci (2015)

Bottom Line: In contrast, the enzyme is undetectable in most astrocytes and microglia.As dysfunction of the ubiquitin proteasome system (UPS) has been linked to many age-related neurological diseases, we compared UbcM2 expression levels in young versus aged wild-type mice and found a global decrease in expression in aged brains, with reductions of 10 % or greater in five substructures (cerebellar granule cell layer, primary motor cortex, olfactory nucleus, superior colliculus, and secondary visual cortex).These studies represent the first protein expression profiling of a ubiquitin-conjugating enzyme in the brain and support the notion that deficits in protein degradation and proteostasis associated with neurodegenerative diseases may be, in part, attributable to age-dependent reductions in the enzymatic machinery of the UPS.

View Article: PubMed Central - PubMed

Affiliation: Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK, USA. larabeec@omrf.org.

ABSTRACT

Background: UbcM2 is a ubiquitin-conjugating enzyme with roles in the turnover of damaged and misfolded proteins, cell cycle progression, development, and regulation of the antioxidant transcription factor, Nrf2. Recent screens have identified binding partners of the enzyme that are associated with various neurodegenerative diseases, and our previous studies have shown that UbcM2 is enriched in retina and brain.

Results: In the current study, we characterized UbcM2 protein expression in various structures and cell types in the murine brain. Immunofluorescence analysis of paraffin-embedded brain sections revealed that UbcM2 is ubiquitously expressed throughout the brain, is enriched in hindbrain and cortex, and is robustly expressed in neurons. In contrast, the enzyme is undetectable in most astrocytes and microglia. As dysfunction of the ubiquitin proteasome system (UPS) has been linked to many age-related neurological diseases, we compared UbcM2 expression levels in young versus aged wild-type mice and found a global decrease in expression in aged brains, with reductions of 10 % or greater in five substructures (cerebellar granule cell layer, primary motor cortex, olfactory nucleus, superior colliculus, and secondary visual cortex).

Conclusions: These studies represent the first protein expression profiling of a ubiquitin-conjugating enzyme in the brain and support the notion that deficits in protein degradation and proteostasis associated with neurodegenerative diseases may be, in part, attributable to age-dependent reductions in the enzymatic machinery of the UPS.

No MeSH data available.


Related in: MedlinePlus

UbcM2 expression is decreased in aged mouse brains. A Representative photomicrographs showing decreased UbcM2 expression in aged (b, d, f, h, j) relative to young control (a, c, e, g, i) brains in the 5 structures with >10 % differences. 20×, size bar 30 μm. B Average expression of UbcM2 in whole brain, consisting of the analysis of 22 substructures, indicating a 5.5 % global decrease in aged brain relative to young control. n = 5 in triplicate; p value = 0.046. C Average UbcM2 expression in the 5 substructures that exhibited a >10 % decrease. Asterisks denote p < 0.05. CB (cerebellum granule cells), MC1 (primary motor cortex), ON (olfactory nucleus), SC (superior colliculus), VC2 (secondary visual cortex)
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Fig4: UbcM2 expression is decreased in aged mouse brains. A Representative photomicrographs showing decreased UbcM2 expression in aged (b, d, f, h, j) relative to young control (a, c, e, g, i) brains in the 5 structures with >10 % differences. 20×, size bar 30 μm. B Average expression of UbcM2 in whole brain, consisting of the analysis of 22 substructures, indicating a 5.5 % global decrease in aged brain relative to young control. n = 5 in triplicate; p value = 0.046. C Average UbcM2 expression in the 5 substructures that exhibited a >10 % decrease. Asterisks denote p < 0.05. CB (cerebellum granule cells), MC1 (primary motor cortex), ON (olfactory nucleus), SC (superior colliculus), VC2 (secondary visual cortex)

Mentions: As the function and efficiency of the UPS decline with age (reviewed in [21, 22]), we next compared the expression levels of UbcM2 in the brains of young and aged mice. Young mice were 1–4 months old, and aged mice ranged from 10–25 months. Sagittal brain sections were examined for neuronal UbcM2 expression as measured by average cellular α-UbcM2-derived fluorescence intensity in NeuN-positive nuclei. An analysis consisting of 22 distinct substructures revealed a modest but statistically significant global decrease of UbcM2 expression of 5.5 % (p value = 0.046) in aged animals as compared to their strain-matched, younger counterparts (Fig. 4A, B; Table 1). Five substructures in particular (cerebellar granule cell layer, primary motor cortex, olfactory nucleus, superior colliculus, and secondary visual cortex) exhibited statistically significant decreases of 10 % or more as a function of age (Fig. 4A, C; Table 1, italic entries).Fig. 4


Expression profiling of the ubiquitin conjugating enzyme UbcM2 in murine brain reveals modest age-dependent decreases in specific neurons.

Larabee CM, Georgescu C, Wren JD, Plafker SM - BMC Neurosci (2015)

UbcM2 expression is decreased in aged mouse brains. A Representative photomicrographs showing decreased UbcM2 expression in aged (b, d, f, h, j) relative to young control (a, c, e, g, i) brains in the 5 structures with >10 % differences. 20×, size bar 30 μm. B Average expression of UbcM2 in whole brain, consisting of the analysis of 22 substructures, indicating a 5.5 % global decrease in aged brain relative to young control. n = 5 in triplicate; p value = 0.046. C Average UbcM2 expression in the 5 substructures that exhibited a >10 % decrease. Asterisks denote p < 0.05. CB (cerebellum granule cells), MC1 (primary motor cortex), ON (olfactory nucleus), SC (superior colliculus), VC2 (secondary visual cortex)
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Fig4: UbcM2 expression is decreased in aged mouse brains. A Representative photomicrographs showing decreased UbcM2 expression in aged (b, d, f, h, j) relative to young control (a, c, e, g, i) brains in the 5 structures with >10 % differences. 20×, size bar 30 μm. B Average expression of UbcM2 in whole brain, consisting of the analysis of 22 substructures, indicating a 5.5 % global decrease in aged brain relative to young control. n = 5 in triplicate; p value = 0.046. C Average UbcM2 expression in the 5 substructures that exhibited a >10 % decrease. Asterisks denote p < 0.05. CB (cerebellum granule cells), MC1 (primary motor cortex), ON (olfactory nucleus), SC (superior colliculus), VC2 (secondary visual cortex)
Mentions: As the function and efficiency of the UPS decline with age (reviewed in [21, 22]), we next compared the expression levels of UbcM2 in the brains of young and aged mice. Young mice were 1–4 months old, and aged mice ranged from 10–25 months. Sagittal brain sections were examined for neuronal UbcM2 expression as measured by average cellular α-UbcM2-derived fluorescence intensity in NeuN-positive nuclei. An analysis consisting of 22 distinct substructures revealed a modest but statistically significant global decrease of UbcM2 expression of 5.5 % (p value = 0.046) in aged animals as compared to their strain-matched, younger counterparts (Fig. 4A, B; Table 1). Five substructures in particular (cerebellar granule cell layer, primary motor cortex, olfactory nucleus, superior colliculus, and secondary visual cortex) exhibited statistically significant decreases of 10 % or more as a function of age (Fig. 4A, C; Table 1, italic entries).Fig. 4

Bottom Line: In contrast, the enzyme is undetectable in most astrocytes and microglia.As dysfunction of the ubiquitin proteasome system (UPS) has been linked to many age-related neurological diseases, we compared UbcM2 expression levels in young versus aged wild-type mice and found a global decrease in expression in aged brains, with reductions of 10 % or greater in five substructures (cerebellar granule cell layer, primary motor cortex, olfactory nucleus, superior colliculus, and secondary visual cortex).These studies represent the first protein expression profiling of a ubiquitin-conjugating enzyme in the brain and support the notion that deficits in protein degradation and proteostasis associated with neurodegenerative diseases may be, in part, attributable to age-dependent reductions in the enzymatic machinery of the UPS.

View Article: PubMed Central - PubMed

Affiliation: Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK, USA. larabeec@omrf.org.

ABSTRACT

Background: UbcM2 is a ubiquitin-conjugating enzyme with roles in the turnover of damaged and misfolded proteins, cell cycle progression, development, and regulation of the antioxidant transcription factor, Nrf2. Recent screens have identified binding partners of the enzyme that are associated with various neurodegenerative diseases, and our previous studies have shown that UbcM2 is enriched in retina and brain.

Results: In the current study, we characterized UbcM2 protein expression in various structures and cell types in the murine brain. Immunofluorescence analysis of paraffin-embedded brain sections revealed that UbcM2 is ubiquitously expressed throughout the brain, is enriched in hindbrain and cortex, and is robustly expressed in neurons. In contrast, the enzyme is undetectable in most astrocytes and microglia. As dysfunction of the ubiquitin proteasome system (UPS) has been linked to many age-related neurological diseases, we compared UbcM2 expression levels in young versus aged wild-type mice and found a global decrease in expression in aged brains, with reductions of 10 % or greater in five substructures (cerebellar granule cell layer, primary motor cortex, olfactory nucleus, superior colliculus, and secondary visual cortex).

Conclusions: These studies represent the first protein expression profiling of a ubiquitin-conjugating enzyme in the brain and support the notion that deficits in protein degradation and proteostasis associated with neurodegenerative diseases may be, in part, attributable to age-dependent reductions in the enzymatic machinery of the UPS.

No MeSH data available.


Related in: MedlinePlus