ABSTRACT
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is the most serious form of degenerative motor neuron disease in adults, characterized by upper and lower motor neuron degeneration, skeletal muscle atrophy, paralysis, and death. High prevalence of malnutrition and weight loss adversely affect quality of life. Moreover, two thirds of patients develop a hypermetabolism of unknown cause, leading to increased resting energy expenditure. Inasmuch as lipids are the major source of energy for muscles, we determined the status of lipids in a population of patients with ALS and investigated whether lipid contents may have an impact on disease progression and survival. METHODS: Blood concentrations of triglycerides, cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were measured in a cohort of 369 patients with ALS and compared to a control group of 286 healthy subjects. Postmortem histologic examination was performed on liver specimens from 59 other patients with ALS and 16 patients with Parkinson disease (PD). RESULTS: The frequency of hyperlipidemia, as revealed by increased plasma levels of total cholesterol or LDL, was twofold higher in patients with ALS than in control subjects. As a result, steatosis of the liver was more pronounced in patients with ALS than in patients with PD. Correlation studies demonstrated that bearing an abnormally elevated LDL/HDL ratio significantly increased survival by more than 12 months. CONCLUSIONS: Hyperlipidemia is a significant prognostic factor for survival of patients with amyotrophic lateral sclerosis. This finding highlights the importance of nutritional intervention strategies on disease progression and claims our attention when treating these patients with lipid-lowering drugs.
Subject(s)
Amyotrophic Lateral Sclerosis/epidemiology , Amyotrophic Lateral Sclerosis/metabolism , Cytoprotection , Dyslipidemias/epidemiology , Dyslipidemias/metabolism , Lipid Metabolism , Adult , Aged , Cholesterol/blood , Comorbidity , Dyslipidemias/physiopathology , Fatty Liver/epidemiology , Fatty Liver/metabolism , Fatty Liver/pathology , Female , Humans , Lipoproteins, LDL/blood , Male , Middle Aged , Muscle, Skeletal/innervation , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Nutritional Support/standards , Prevalence , Survival Rate , Up-Regulation/physiologyABSTRACT
Nicastrin is a recently discovered protein interacting with presenilins and the beta-amyloid precursor protein, the proteins playing key roles in Alzheimer's disease and which, when mutated, appear responsible for early-onset familial forms of Alzheimer's disease. Nicastrin was reported to modulate beta-amyloid production, a phenotype affected differently by missense mutations or deletions of a conserved hydrophilic domain. In addition to such a function, nicastrin was recently suggested to possess putative catalytic activity based on its sequence homology with enzymes of the aminopeptidase family. We set up stably transfected human HEK293 cells expressing either wild-type or mutated nicastrins and we show that these proteins do not exhibit aminopeptidase M- and B-like activities.
