PERK activation preserves the viability and function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases.

Remyelination occurs in multiple sclerosis (MS) lesions but is generally considered to be insufficient. One of the major challenges in MS research is to understand the causes of remyelination failure and to identify therapeutic targets that promote remyelination. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum stress modulates cell viability and function under stressful conditions. There is evidence that PERK is activated in remyelinating oligodendrocytes in demyelinated lesions in both MS and its animal model, experimental autoimmune encephalomyelitis (EAE). In this study, we sought to determine the role of PERK signaling in remyelinating oligodendrocytes in MS and EAE using transgenic mice that allow temporally controlled activation of PERK signaling specifically in oligodendrocytes. We demonstrated that persistent PERK activation was not deleterious to myelinating oligodendrocytes in young, developing mice or to remyelinating oligodendrocytes in cuprizone-induced demyelinated lesions. We found that enhancing PERK activation, specifically in (re)myelinating oligodendrocytes, protected the cells and myelin against the detrimental effects of interferon-γ, a key proinflammatory cytokine in MS and EAE. More important, we showed that enhancing PERK activation in remyelinating oligodendrocytes at the recovery stage of EAE promoted cell survival and remyelination in EAE demyelinated lesions. Thus, our data provide direct evidence that PERK activation cell-autonomously enhances the survival and preserves function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases.

Extensive aspartoacylase expression in the rat central nervous system.

Aspartoacylase (ASPA) catalyzes deacetylation of N-acetylaspartate (NAA) to generate acetate and aspartate. Mutations in the gene for ASPA lead to reduced acetate availability in the CNS during development resulting in the fatal leukodystrophy Canavan disease. Highly specific polyclonal antibodies to ASPA were used to examine CNS expression in adult rats. In white matter, ASPA expression was associated with oligodendrocyte cell bodies, nuclei, and some processes, but showed a dissimilar distribution pattern to myelin basic protein and oligodendrocyte specific protein. Microglia expressed ASPA in all CNS regions examined, as did epiplexus cells of the choroid plexus. Pial and ependymal cells and some endothelial cells were ASPA positive, as were unidentified cellular nuclei throughout the CNS. Astrocytes did not express ASPA in their cytoplasm. In some fiber pathways and nerves, particularly in the brainstem and spinal cord, the axoplasm of many neuronal fibers expressed ASPA, as did some neurons. Acetyl coenzyme A synthase immunoreactivity was also observed in the axoplasm of many of the same fiber pathways and nerves. All ASPA-immunoreactive elements were unstained in brain sections from tremor rats, an ASPA-null mutant. The strong expression of ASPA in oligodendrocyte cell bodies is consistent with a lipogenic role in myelination. Strong ASPA expression in cell nuclei is consistent with a role for NAA-derived acetate in nuclear acetylation reactions, including histone acetylation. Expression of ASPA in microglia may indicate a role in lipid synthesis in these cells, whereas expression in axons suggests that some neurons can both synthesize and catabolize NAA.

Tremor of the mouth floor and anti-glutamic acid decarboxylase autoantibodies.

Involuntary movements of the mouth can present as palatal tremor, which is frequently associated with hypertrophy of the inferior olivary nucleus and can be accompanied by contraction of other muscles of the head. We report the case of a 39-year-old man with autoimmune thyroiditis and diabetes who complained of involuntary rhythmic tremor involving the muscles of the floor of the mouth, which interfered with breathing and swallowing. Cerebrospinal fluid (CSF) examination showed the presence of oligoclonal bands and screening for anti-neuronal antibodies revealed high titres of anti-glutamic acid decarboxylase autoantibodies (GAD-Ab). Tremor responded to treatment with benzodiazepines. The correlation between the tremor and antibody positivity is unclear although an alteration of the gabaergic system mediated by the antibodies may be hypothesised on the basis of an inflammatory CSF profile.

Tyrosine hydroxylase deficiency: clinical manifestations of catecholamine insufficiency in infancy.

Inborn errors of catecholamine biosynthesis are rare but of great interest as they are genetic disorders, and in some, treatment may completely reverse severe neurological abnormalities. They also provide insights into the action of the biogenic amines in the developing brain. We describe the clinical course of an infant with tyrosine hydroxylase (TOH) deficiency over a 30-month period. The parents are consanguineous, and genetic analysis revealed the infant to be homozygous for the common G698A mutation in the TOH gene. TOH deficiency can be seen as a model of pure catecholamine deficiency. Experimental evidence, reports of other disorders of biogenic amines, and our experience with this infant suggest that the symptoms of catecholamine deficiency in infancy can be broadly subdivided. Signs of dopamine deficiency include tremor, hypersensitivity to levadopa (L-dopa) therapy, oculogyric crises, akinesia, rigidity, and dystonia. Manifestations of norepinephrine deficiency include ptosis, miosis, profuse oropharyngeal secretions, and postural hypotension. Hypersensitivity to L-dopa was a particular management problem in this infant.

Effects of p-chlorophenylalanine on striatal acetylcholinesterase activity and on biogenic amine levels in nuclei raphe and caudate-putamen during physostigmine-induced tremor in rats.

The biochemical mechanism underlying tremor is unknown. We investigated the effects of p-chlorophenylalanine (pCPA), a serotonin (5-HT) depletor, on the neurochemical processes in nuclei raphe dorsalis (NRD) and caudatus putamen (NCP) paralleling physostigmine-induced tremor in rats. Peak of physostigmine tremor correlated with increase in 5-HT in NRD and NCP, and a decrease in striatal dopamine (DA), as assayed employing high pressure liquid chromotography-electrochemistry. Administration of pCPA caused significant decrease in DA, norepinephrine (NE) and 5-HT levels in both the nuclei, without affecting striatal NE content and acetylcholinesterase activity. pCPA pretreatment significantly inhibited physostigmine-induced tremor and blocked corresponding increase in the levels of 5-HT in NRD and NCP. These results indicate involvement of central 5-HT, but not DA or NE, in the genesis of physostigmine tremor.

Erythrocyte superoxide dismutase activity differs in clinical subgroups of Parkinson's disease patients.

There is controversy as to whether there are clinical subgroups in Parkinson's disease (PD). Six tremor-dominant and six bradykinesia-dominant patients identified among 29 cases with PD were compared in terms of erythrocyte superoxide dismutase (SOD) activity and several clinical variables. Erythrocyte SOD activity in tremor-dominant patients was higher than in bradykinesia-dominant patients. According to our preliminary results obtained from small number of patients, the difference of SOD activity in clinically distinct subgroups suggests there may be separate clinical subgroups of PD which can be differentiated by a biological marker.

A deletion in the long arm of chromosome 18 in a child with serum carnosinase deficiency.

The dipeptides carnosine and anserine, found exclusively in meats, are hydrolyzed in serum by the enzyme carnosinase. Several reports of serum carnosinase deficiency describe a variable phenotype, which ranges from normal to severe psychomotor retardation, hypotonia, and myoclonic seizures in the first year of life. We report the case of a 30-mo-old girl with hypotonia, developmental delays, and tremor. Although consuming nominal quantities of meal, she excreted large amounts of carnosine and anserine. A strict meat-free diet ameliorated, but did not eliminate, these abnormalities. Serum carnosinase activity was found to be extremely low. Analysis of this child's chromosomes revealed a terminal deletion of chromosome 18 with breakpoint at q21.3. Neither parent exhibited this deletion, suggesting it was generated de novo in the patient or in a parental germ cell. Molecular studies showed that the patient's paternal chromosome 18 was deleted. Urinary carnosine excretion and serum carnosinase activity were normal in the patient's father. The mother had low carnosinase activity. The patient's brother exhibited moderate hypercarnosinuria and intermediate enzyme activity, consistent with the carrier state for carnosinase deficiency. Cumulatively, these findings suggest that the locus for this enzyme resides on the distal long arm of chromosome 18, and they are consistent with an unusual mechanism for the inheritance of this, typically autosomal recessive, condition. We conclude that this patient is likely hemizygous for the defect, having received the deficiency allele from her mother and, by virtue of the chromosomal deletion, no allele from her father. This represents the first report of a chromosomal abnormality in association with serum carnosinase deficiency and should aid in further localization of the gene encoding serum carnosinase.

Calcium-activated neutral protease (CANP) in normal and dysmyelinating mutant paralytic tremor rabbit myelin.

Calcium-activated neutral protease (CANP) in normal and dysmyelinating mutant, paralytic tremor (PT) rabbit myelin and premyelin fractions was studied using immature (4-5 wk) or adult animals. The enzyme was estimated by determination of its catalytic activity as well as by using immunoblot analysis after SDS-PAGE separation. The presence of two forms of CANP--one activated by calcium in the micromolar concentration (mu CANP) range and the other exhibiting low calcium sensitivity in the millimolar concentration range (m-CANP)--was found in the myelin and premyelin fractions. The developmental pattern of the enzyme activity was different for each of these two enzyme isoforms depending on the fraction studied. The higher activity on CANP (both isoforms) found in PT myelin and premyelin could be related to delayed myelination and/or to the higher turnover rate of already formed myelin. These results suggest complex and specific roles for these isoenzymes during myelin formation as is discussed further in this article. Our results confirm the extensive degradation of myelin basic protein (MBP), proteolipid protein (PLP), and, to a lesser extent, the other myelin proteins by endo- and exogenous CANP. This degradation process was significantly elevated in PT rabbit myelin. Moreover as was shown by two-dimensional gel electrophoresis, calcium-controlled proteolysis in nonmutant rabbits affected the net-charge of MBP in a manner similar to that reported for PT myelin, suggesting the possible involvement of CANP in the generation of charge isomers of MBP.

Activity of serum creatine kinase, lactate dehydrogenase and LD isoenzymes in piglets affected with congenital tremor: a case report.

The activities of serum creatine kinase (CK), lactate dehydrogenase (LD) and LD isoenzymes were studied in 14 Prestice black pied pigs from a herd affected with congenital tremor. Mean CK activity was 19.57 +/- 3.56 mu kat.l-1 for 6 adult pigs, and it was 21.03 +/- 1.33 mu kat.l-1 and 20.42 +/- 1.23 mu kat.l-1 for the affected (n = 5) and control (n = 3) piglets, respectively. No significant differences were demonstrable between the groups in CK activity. Total serum LD and LD-4 as well as LD-5 isoenzyme activities were higher in sows. Piglets affected with congenital tremor showed an increase in total LD enzyme and LD-5 isoenzyme activity. It is concluded that no relationship exists between congenital tremor and serum CK activity in piglets. At the same time, there is a positive relationship between congenital tremor and significantly (P < 0.01) elevated LD enzyme and LD-5 isoenzyme activity. The results allow us to suggest that total lactate dehydrogenase and LD-5 isoenzyme activities could be used as biological markers of congenital tremor in piglets.

Inhibition of ornithine decarboxylase alters neurological responsiveness to a tremorigen.

Difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (ODC; 200-800 mg/kg, s.c.), to rats has no detectable behavioral effects using a battery of tests to assess sensorimotor function. In contrast, the induction of tremor by chlordecone, a neurotoxic agent that affects neuronal ionic processes, is significantly attenuated by pretreatment with DFMO. The effects of DFMO on chlordecone-induced tremor were reversed by pretreatment with putrescine. DFMO had no effects on p,p'-DDT, a tremorigen having a mechanism of action different from chlordecone. These findings imply that polyamines may play a role in select neuronal processes.

CFS hydroxylase cofactor levels in some neurological diseases.

The cerebrospinal fluid concentration of hydroxylase cofactor has been measured in patients with Parkinson's disease, the Shy-Drager and Steele-Richardson syndromes, adult onset focal dystonia, essential tremor, Huntington's disease and presenile dementia. The results were compared with age matched controls and low values were demonstrated for all disease groups studied except for focal dystonia.

Genotype dependence of monoamine oxidase in inbred strains of mice.

MAO activity was found to be influenced by the genotype or strain of mouse up to 20 days of age. The strain differences observed may derive from different rates of brain development. A number of neurological mutations comprizing three pathological classes had no effect on MAO.

Cerebral acid hydrolase activities: comparison in "quaking" and normal mice.

The activity of several acid hydrolase enzymes was determined in whole brain homogenates of adult "quaking" and normal mice. A striking decrease was found in alpha-mannosidase and, to a lesser extent, aryl sulfatase levels in the samples from the mutant animals. The activities of the other "lyso-somal" enzymes were only slightly lowered.