alpha-synuclein and Niemann-Pick-Diseases

Evaluation of motor deficits in rodents is mostly restricted to limb motor tests that are often high stressors for the animals.. To test rodents for orofacial motor impairments in a stress-free environment, we established the pasta gnawing test by measuring the biting noise of mice that eat a piece of spaghetti. Two parameters were evaluated, the biting speed and the biting peaks per biting episode. To evaluate the power of this test compared to commonly used limb motor and muscle strength tests, three mouse models of Parkinson's disease, amyotrophic lateral sclerosis and Niemann-Pick disease were tested in the pasta gnawing test, RotaRod and wire suspension test.. Our results show that the pasta gnawing test reliably displays orofacial motor deficits.. The test is especially useful as additional motor test in early onset disease models, since it shows first deficits later than the RotaRod or wire suspension test. The test depends on a voluntary eating behavior of the animal with only a short-time food deprivation and should thus be stress-free.. The pasta gnawing test represents a valuable tool to analyze orofacial motor deficits in different early onset disease models.

Topics: alpha-Synuclein; Amyotrophic Lateral Sclerosis; Animals; Craniofacial Abnormalities; Disease Models, Animal; DNA-Binding Proteins; Exercise Test; Humans; Intracellular Signaling Peptides and Proteins; Mastication; Mice; Mice, Transgenic; Motor Activity; Muscle Strength; Niemann-Pick C1 Protein; Niemann-Pick Diseases; Parkinson Disease; Proteins; Psychomotor Performance; Reaction Time; Rotarod Performance Test; Statistics, Nonparametric

Niemann-Pick type C1 disease (NPC1) is an autosomal recessive neurovisceral storage disease caused by the mutation of NPC1 gene, resulting in perturbed intracellular transport of unesterified cholesterol. In NPC1, early-onset tauopathy is a constant feature. In addition, in NPC1 patients with ApoE epsilon4 homozygosity, deposition of A beta occurs mimicking Alzheimer disease (AD). Since AD is frequently associated with neuronal expression of alpha-synuclein, we investigated phosphorylated alpha-synuclein (psyn) immunoreactivity in the brains of 12 NPC1 patients, ages at death ranging from 9 months to 55 years. Psyn immunoreactivity was demonstrated in the perikarya of storage neurons and oligodendroglia in 10 cases. The immunoreactivity appeared more intense in subjects who had the ApoE epsilon4 allele. Lewy bodies were found in the substantia nigra in 2 of these cases. The psyn immunoreactivity was most intense in the substantia nigra where tauopathy was most severe. Phosphorylated tau and alpha-synuclein frequently colocalized. This study first documents alpha-synucleinopathy in NPC1. This observation suggests that the defect in intracellular cholesterol trafficking in NPC1 may provoke aberrant phosphorylation of alpha-synuclein and tau, and that this phosphorylation is enhanced by the ApoE epsilon4 allele. Thus, elucidation of metabolic pathways in NPC1 could provide clues to common mechanisms associated with neurodegeneration.

Topics: Adolescent; Adult; alpha-Synuclein; Apolipoproteins E; Brain; Child; Child, Preschool; Female; Genotype; Humans; Immunohistochemistry; Infant; Lewy Bodies; Male; Microscopy, Confocal; Middle Aged; Nerve Tissue Proteins; Neuroglia; Neurons; Niemann-Pick Diseases; Phosphorylation; Synucleins