Prominent pancreatic endocrinopathy and altered control of food intake disrupt energy homeostasis in prion diseases

Abstract

Prion diseases are fatal neurodegenerative diseases that can induce endocrinopathies. The basis of altered endocrine function in prion diseases is not well understood, and the purpose of this study was to investigate the spatiotemporal relationship between energy homeostasis and prion infection in hamsters inoculated with either the 139H strain of scrapie agent, which induces preclinical weight gain, or the HY strain of transmissible mink encephalopathy (TME), which induces clinical weight loss. Temporal changes in body weight, feed, and water intake were measured as well as both non-fasted and fasted concentrations of serum glucose, insulin, glucagon, b-ketones, and leptin. In 139H scrapie-infected hamsters, polydipsia, hyperphagia, non-fasted hyperinsulinemia with hyperglycemia, and fasted hyperleptinemia were found at preclinical stages and are consistent with an anabolic syndrome that has similarities to type II diabetes mellitus and/or metabolic syndrome X. In HY TME-infected hamsters, hypodipsia, hypersecretion of glucagon (in both non-fasted and fasted states), increased fasted b-ketones, fasted hypoglycemia, and suppressed non-fasted leptin concentrations were found while feed intake was normal. These findings suggest a severe catabolic syndrome in HY TME infection mediated by chronic increases in glucagon secretion. In both models, alterations of pancreatic endocrine function were not associated with PrP Sc deposition in the pancreas. The results indicate that prominent endocrinopathy underlies alterations in body weight, pancreatic endocrine function, and intake of food. The prion-induced alterations of energy homeostasis in 139H scrapie-or HY TME-infected hamsters could occur within areas of the hypothalamus that control food satiety and/or within autonomic centers that provide neural outflow to the pancreas.

Distribution of Peripheral PrPSc in Sheep with Naturally Acquired Scrapie

“…The results reported herein clearly show that PrP Sc deposits in the pancreas are associated with the PNS; however, in natural and experimental CWD infections, PrP Sc has been observed in the islets of Langerhans [27], [29]. It has been suggested that disturbances in endocrine homeostasis that have been described for several TSE, might be the result of targeting the prion infection to the peripheral and/or central endocrine system [30]. However, a relationship between the alteration of pancreatic endocrine function and PrP Sc deposition in the islets of Langerhans has not been clearly shown [30].…”

“…It has been suggested that disturbances in endocrine homeostasis that have been described for several TSE, might be the result of targeting the prion infection to the peripheral and/or central endocrine system [30]. However, a relationship between the alteration of pancreatic endocrine function and PrP Sc deposition in the islets of Langerhans has not been clearly shown [30]. Our results suggest that PrP Sc deposition in the PNS (which innervates endocrine organs) may also participate in prion-induced endocrinopathies.…”

PrPSc formation and clearance as determinants of prion tropism

“…All samples were digested with PK prior to Western blot analysis. A significant (p<0.05) fold increase in PrP Sc abundance (Fig 4, panel A, lanes 4 and 6) was observed in the HY TME (3.16±0.14) and 139H (3.02±0.41) seeded groups compared to the starting material following one round of PMCA (Fig 4, panel A, lanes 3 and 5) indicating that LRS tissue can support PrP Sc formation similar to what has been observed in vivo [27,49]. A significant (p<0.05) 1.33±0.09 and 1.29±0.11 fold increase in PrP Sc abundance was observed in PMCA reactions seeded with DY TME brain homogenate (Fig 4, panel A, lane 8) or detergent enriched PK digested DY PrP-res (Fig 4, panel A, lane 10) respectively, compared to the starting reactions (Fig 4, panel A, lanes 7 and 9).…”

Stabilization of a Prion Strain of Synthetic Origin Requires Multiple Serial Passages

“…Obesity was previously reported in animals inoculated with 139H hamster-adapted scrapie agent (32). However, unlike 139H, in addition to overall weight gain, SSLOW-inoculated animals exhibited significant individual weight fluctuation during the clinical stage (Fig.…”