Reducing the lipase LIPE in mutant α-synuclein mice improves Parkinson-like deficits and reveals sex differences in fatty acid metabolism.

Impaired lipid metabolism is a risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and can shift the physiological α-synuclein (αS) tetramer-monomer (T:M) ratio toward aggregation prone monomers. A resultant increase in phospho-serine 129+ αS monomers associating with excess mono- and polyunsaturated fatty acids contributes to the αS aggregation. We previously reported that decreasing the release of monounsaturated fatty acids (MUFAs) by reducing or inhibiting the hormone sensitive lipase (LIPE) reversed pathologic αS phosphorylation and improved soluble αS homeostasis in cultured αS triplication PD neurons and reduced DAergic neurodegeneration in a C.elegans αS model. However, assessing LIPE as a potential therapeutic target for progressive PD motor phenotypes has not been investigated. 3K αS mice, representing a biochemical and neuropathological amplification of the E46K fPD-causing mutation, have decreased αS T:M ratios, lipidic aggregates, and a L-DOPA responsive PD-like motor syndrome. Here, we reduced LIPE by crossings of 3K mice with LIPE null mice, which attenuated motor deficits in male LIPE+/- knockdown (LKD)-3K mice. Heterozygous LIPE reduction was associated with an improved αS T:M ratio, and dopaminergic neurotransmitter levels and fiber densities. In female 3K-LKD mice, an increase in pS129+ and larger lipid droplets (LDs) likely decreased the benefits seen in males. Reducing LIPE decreased MUFA release from neutral lipid storage, thereby reducing MUFA in phospholipid membranes with which αS interacts. Our study highlights fatty acid turnover as a therapeutic target for Lewy body diseases and support LIPE as a promising target in males. LIPE regulation represents a novel approach to mitigate PD and DLB risk and treat disease.

Occupational and industrial toxin exposures and the gastrointestinal tract. Gastrointestinal Toxicology Subcommittee of the American College of Gastroenterology Patient Care Committee.

The subcommittee on Gastrointestinal Toxicology of the Patient Care Committee of the American College of Gastroenterology has reviewed potential effects of exposures to occupational and industrial hazards on the gastrointestinal tract, liver and pancreas. This review is presented to 1) share clinical data concerning gastrointestinal toxicology, 2) emphasize the paucity of available information to the practicing clinician, and 3) stimulate basic research interest in this field.

Hereditary telangiectasia manifested as gastrointestinal bleeding without external visible telangiectasia.

Gastrointestinal bleeding is one of the most common problems confronting the physician. In most instances, the source of the bleeding is easily identified, e.g., peptic ulcer disease, bleeding esophageal varices or a colonic lesion. Recurrent gastrointestinal bleeding, however, represents one of the major enigmas confronting the practicing physician. The patient experiences intermittent episodes of weakness, easy fatigability and anemia with occult blood in the stool. Multiple barium radiographic examinations and often endoscopy and exploratory laparotomy are unrevealing as to the etiology of the bleeding. We have had occasion to investigate three such patients. Multiple evaluations of these individuals did not reveal the source of the bleeding until many years later--Rendu-Osler-Weber Disease (ROW). At the time of their evaluations these patients did not reveal the usual telangiectatic areas present on the skin and oral mucous membrane. The diagnosis was suggested by the presence of multiple gastric mucosal telangiectasia identified by gastroscopic examination. This report emphasizes the need for thorough endoscopic evaluation of patients with gastrointestinal bleeding and describes the gastroscopic findings that indicated hereditary telangiectasia as the probable source of bleeding from the gastrointestinal tract.

The management of foreign affairs of the GI tract.

The flexible fiberoptic endoscope has not been employed consistently in the removal of foreign bodies from the gastrointestinal tract due to size limitations of the forceps and biopsy channel. The following report describes a technique for extracting large irregular objects from the upper-gastrointestinal tract, employing the polypectomy snare. It is a safe and reproducible procedure for the careful extraction of impacted objects.