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Altered hypothalamic protein expression in a rat model of Huntington's disease.

Cong WN, Cai H, Wang R, Daimon CM, Maudsley S, Raber K, Canneva F, von Hörsten S, Martin B - PLoS ONE (2012)

Bottom Line: Our results demonstrate that there are significant alterations in HD rat hypothalamic protein expression such as glial fibrillary acidic protein (GFAP), heat shock protein-70, the oxidative damage protein glutathione peroxidase (Gpx4), glycogen synthase1 (Gys1) and the lipid synthesis enzyme acylglycerol-3-phosphate O-acyltransferase 1 (Agpat1).These early metabolic and lipid alterations are likely prodromal signs of hypothalamic dysfunction.Gaining a greater understanding of the hypothalamic and metabolic alterations that occur in HD, could lead to the development of novel therapeutics for early interventional treatment of HD.

View Article: PubMed Central - PubMed

Affiliation: Metabolism Unit, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.

ABSTRACT
Huntington's disease (HD) is a neurodegenerative disorder, which is characterized by progressive motor impairment and cognitive alterations. Changes in energy metabolism, neuroendocrine function, body weight, euglycemia, appetite function, and circadian rhythm can also occur. It is likely that the locus of these alterations is the hypothalamus. We used the HD transgenic (tg) rat model bearing 51 CAG repeats, which exhibits similar HD symptomology as HD patients to investigate hypothalamic function. We conducted detailed hypothalamic proteome analyses and also measured circulating levels of various metabolic hormones and lipids in pre-symptomatic and symptomatic animals. Our results demonstrate that there are significant alterations in HD rat hypothalamic protein expression such as glial fibrillary acidic protein (GFAP), heat shock protein-70, the oxidative damage protein glutathione peroxidase (Gpx4), glycogen synthase1 (Gys1) and the lipid synthesis enzyme acylglycerol-3-phosphate O-acyltransferase 1 (Agpat1). In addition, there are significant alterations in various circulating metabolic hormones and lipids in pre-symptomatic animals including, insulin, leptin, triglycerides and HDL, before any motor or cognitive alterations are apparent. These early metabolic and lipid alterations are likely prodromal signs of hypothalamic dysfunction. Gaining a greater understanding of the hypothalamic and metabolic alterations that occur in HD, could lead to the development of novel therapeutics for early interventional treatment of HD.

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Related in: MedlinePlus

LSI correlation analysis of altered hypothalamic proteins in TgHD rats.LSI analysis of tgHD significantly-regulated hypothalamic proteins was performed using the following search terms: Huntingtin, Chorea, Diabetes and Insulin. Red signifies up-regulated proteins and green signifies down-regulated proteins.
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pone-0047240-g009: LSI correlation analysis of altered hypothalamic proteins in TgHD rats.LSI analysis of tgHD significantly-regulated hypothalamic proteins was performed using the following search terms: Huntingtin, Chorea, Diabetes and Insulin. Red signifies up-regulated proteins and green signifies down-regulated proteins.

Mentions: Both up- and down-regulated protein sets identified by iTRAQ were analyzed using the KEGG pathway algorithm. Use of the KEGG pathway algorithm allows for the potential physiological role(s) of significantly altered proteins to be further delineated. We found that a major body of significantly altered proteins in tgHD rats was closely associated with energy metabolism. Calculation of subsequent hybrid scores further revealed that the significantly altered proteins were highly involved in fatty acid metabolism, oxidative phosphorylation, glycolysis/gluconeogenesis, glycerolipid metabolism, PPAR signaling pathway and the insulin signaling pathway (Fig. 8, Table 1). Other significantly altered proteins were strongly associated with cell communication (Focal adhesion, Adherens junction, Gap junction, Tight junction) and neuronal function (Amytrophic Lateral Sclerosis, Long-term depression, Fig. 8, Table 1). To further appreciate the potential hypothalamic pathophysiological ramifications of these protein alterations, we performed LSI analysis on the significantly altered proteins (Fig. 9). LSI analysis revealed that many proteins were significantly correlated to Huntingtin (arfaptin-2 (Arfip2), sacsin (Sacs), heat shock 70 kD protein 1B (Hspa1b), transglutaminase 2 (Tgm2)), chorea (Arfip2, Sacs, disco-interacting protein 2 homolog B (Dip2b)), diabetes (1-acylglycerol-3-phosphate O-acyltransferase 1 (Agpat), glycogen synthase 1 (Gys1), solute carrier family 2(Slc2a1)), and insulin (pyruvate dehydrogenase kinase isozyme 2 (Pdk2), pyruvate kinase 2 (Pkm2), branched chain aminotransferase 2 (Bcat2), carbonic anhydrase 3 (Car3)). In line with the results obtained from the KEGG analysis, upon application of LSI analysis we found that the strongest proteomic representation for tgHD rats was significantly correlated to the energy-related terms ‘diabetes’ and ‘insulin’. A full list of LSI analysis results is provided in Table S3 (up-regulated) and Table S4 (down-regulated).


Altered hypothalamic protein expression in a rat model of Huntington's disease.

Cong WN, Cai H, Wang R, Daimon CM, Maudsley S, Raber K, Canneva F, von Hörsten S, Martin B - PLoS ONE (2012)

LSI correlation analysis of altered hypothalamic proteins in TgHD rats.LSI analysis of tgHD significantly-regulated hypothalamic proteins was performed using the following search terms: Huntingtin, Chorea, Diabetes and Insulin. Red signifies up-regulated proteins and green signifies down-regulated proteins.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3475691&req=5

pone-0047240-g009: LSI correlation analysis of altered hypothalamic proteins in TgHD rats.LSI analysis of tgHD significantly-regulated hypothalamic proteins was performed using the following search terms: Huntingtin, Chorea, Diabetes and Insulin. Red signifies up-regulated proteins and green signifies down-regulated proteins.
Mentions: Both up- and down-regulated protein sets identified by iTRAQ were analyzed using the KEGG pathway algorithm. Use of the KEGG pathway algorithm allows for the potential physiological role(s) of significantly altered proteins to be further delineated. We found that a major body of significantly altered proteins in tgHD rats was closely associated with energy metabolism. Calculation of subsequent hybrid scores further revealed that the significantly altered proteins were highly involved in fatty acid metabolism, oxidative phosphorylation, glycolysis/gluconeogenesis, glycerolipid metabolism, PPAR signaling pathway and the insulin signaling pathway (Fig. 8, Table 1). Other significantly altered proteins were strongly associated with cell communication (Focal adhesion, Adherens junction, Gap junction, Tight junction) and neuronal function (Amytrophic Lateral Sclerosis, Long-term depression, Fig. 8, Table 1). To further appreciate the potential hypothalamic pathophysiological ramifications of these protein alterations, we performed LSI analysis on the significantly altered proteins (Fig. 9). LSI analysis revealed that many proteins were significantly correlated to Huntingtin (arfaptin-2 (Arfip2), sacsin (Sacs), heat shock 70 kD protein 1B (Hspa1b), transglutaminase 2 (Tgm2)), chorea (Arfip2, Sacs, disco-interacting protein 2 homolog B (Dip2b)), diabetes (1-acylglycerol-3-phosphate O-acyltransferase 1 (Agpat), glycogen synthase 1 (Gys1), solute carrier family 2(Slc2a1)), and insulin (pyruvate dehydrogenase kinase isozyme 2 (Pdk2), pyruvate kinase 2 (Pkm2), branched chain aminotransferase 2 (Bcat2), carbonic anhydrase 3 (Car3)). In line with the results obtained from the KEGG analysis, upon application of LSI analysis we found that the strongest proteomic representation for tgHD rats was significantly correlated to the energy-related terms ‘diabetes’ and ‘insulin’. A full list of LSI analysis results is provided in Table S3 (up-regulated) and Table S4 (down-regulated).

Bottom Line: Our results demonstrate that there are significant alterations in HD rat hypothalamic protein expression such as glial fibrillary acidic protein (GFAP), heat shock protein-70, the oxidative damage protein glutathione peroxidase (Gpx4), glycogen synthase1 (Gys1) and the lipid synthesis enzyme acylglycerol-3-phosphate O-acyltransferase 1 (Agpat1).These early metabolic and lipid alterations are likely prodromal signs of hypothalamic dysfunction.Gaining a greater understanding of the hypothalamic and metabolic alterations that occur in HD, could lead to the development of novel therapeutics for early interventional treatment of HD.

View Article: PubMed Central - PubMed

Affiliation: Metabolism Unit, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.

ABSTRACT
Huntington's disease (HD) is a neurodegenerative disorder, which is characterized by progressive motor impairment and cognitive alterations. Changes in energy metabolism, neuroendocrine function, body weight, euglycemia, appetite function, and circadian rhythm can also occur. It is likely that the locus of these alterations is the hypothalamus. We used the HD transgenic (tg) rat model bearing 51 CAG repeats, which exhibits similar HD symptomology as HD patients to investigate hypothalamic function. We conducted detailed hypothalamic proteome analyses and also measured circulating levels of various metabolic hormones and lipids in pre-symptomatic and symptomatic animals. Our results demonstrate that there are significant alterations in HD rat hypothalamic protein expression such as glial fibrillary acidic protein (GFAP), heat shock protein-70, the oxidative damage protein glutathione peroxidase (Gpx4), glycogen synthase1 (Gys1) and the lipid synthesis enzyme acylglycerol-3-phosphate O-acyltransferase 1 (Agpat1). In addition, there are significant alterations in various circulating metabolic hormones and lipids in pre-symptomatic animals including, insulin, leptin, triglycerides and HDL, before any motor or cognitive alterations are apparent. These early metabolic and lipid alterations are likely prodromal signs of hypothalamic dysfunction. Gaining a greater understanding of the hypothalamic and metabolic alterations that occur in HD, could lead to the development of novel therapeutics for early interventional treatment of HD.

Show MeSH
Related in: MedlinePlus