Showing papers by "Lars Olson published in 2000"

NURR1 mutations in cases of schizophrenia and manic-depressive disorder.

Abstract: Transgenic mice lacking the nuclear orphan transcription factor Nur-related receptor 1 (Nurr1) fail to develop mesencephalic dopamine neurons. There is a highly homologous NURR1 gene in humans (formerly known as NOT) which therefore constitutes a good candidate gene for neurologic and psychiatric disorders with an involvement of the dopamine neuron system, such as Parkinson's disease, schizophrenia, and manic-depression. By direct sequencing of genomic DNA, we found two different missense mutations in the third exon of NURR1 in two schizophrenic patients and another missense mutation in the same exon in an individual with manic-depressive disorder. All three mutations caused a similar reduction of in vitro transcriptional activity of NURR1 dimers of about 30–40%. Neither of these amino acid changes, nor any sequence changes whatsoever, were found in patients with Parkinson's disease or control DNA material of normal populations. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:808–813, 2000. © 2000 Wiley-Liss, Inc.

Running and cocaine both upregulate dynorphin mRNA in medial caudate putamen.

Abstract: Physical activities such as long-distance running can be habit forming and associated with a sense of well-being to a degree that justifies comparison with drug-induced addictive behaviours. To understand molecular similarities and dissimilarities controlling these behaviours in humans we compared the effects of running in running wheels to the effects of chronic cocaine or morphine administration on mRNA levels in brain reward pathways in the inbred Fischer and Lewis rat strains. These strains are both inbred from the Sprague-Dawley strain; Lewis rats display a higher preference towards addictive drugs and running than do Fischer rats. After chronic cocaine or running a similar increase of dynorphin mRNA in medial caudate putamen was found in the Lewis rat, suggesting common neuronal adaptations in this brain region to both cocaine and running. Fischer and Lewis rats both responded to cocaine with increased dynorphin mRNA levels in medial caudate putamen. However, only Lewis rats increased dynorphin mRNA after running, possibly reflecting the much higher degree of running by the Lewis strain as compared to the Fischer strain. Moreover, the running-induced upregulation of dynorphin mRNA was blocked by the opioid receptor antagonist naloxone. We suggest that running increases dynorphin mRNA by a mechanism that involves endogenous opioids. The voluntary wheel-running model in rats might be used to study natural reward and compulsive behaviours and possibly also to screen candidate drugs for treatment of compulsive disorders.

Alcohol dehydrogenase alleles in Parkinson's disease

Abstract: Mutations in alcohol dehydrogenase (ADH; EC 1.1.1.1) genes may be of interest in the etiology of Parkinson's disease (PD) because of the important role these enzymes play in retinoid and dopamine metabolism and/or aldehyde detoxification. The location of several alcohol dehydrogenase genes in a cluster on chromosome 4 lends further support to ADH genes being candidates for this disorder, because recently a form of autosomal-dominant parkinsonism has been mapped to this area. We sequenced the promoter and coding regions and part of the introns of the human class IV ADH gene in 10 patients with PD. Seven different polymorphisms were identified. These polymorphisms could be assigned to four alleles (A1-A4). We then determined the frequencies of those four alleles and the wild-type allele in 78 patients with PD and 130 control subjects and found a significant association of the A1 allele with PD (odds ratio = 2.87; 95% confidence interval = 1.35-6.08). In familial cases, the association was strongest (odds ratio = 4.86; 95% confidence interval = 1.89-12.75). Two patients were homozygous for A1 whereas none of the 130 control subjects was found to be homozygous. Our results show an association between a certain ADH4 (formerly known as ADH7 in humans) allele and PD. This suggests a role for genetic variations of ADH4 as risk factors for the development of PD. Our data also show that the observed polymorphisms alone are not sufficient to cause symptoms. Further genetic and/or environmental factors have to be involved.

Neurturin, RET, GFRα-1 and GFRα-2, but not GFRα-3, mRNA are expressed in mice gonads.

Abstract: The gonads are known to produce numerous hormones and also neurotrophins and their receptors. Here we demonstrate expression of glial-cell-line-derived neurotrophic factor (GDNF) family ligands and related receptors in adult mice gonads by in situ hybridization. GDNF mRNA was expressed in the ovary, but was not detectable in testis. Neurturin (NTN), another ligand in this family, gave rise to strong mRNA hybridization signals in a mosaic pattern in the seminiferous tubules of the testis at stages IX–XII and I–II of the cycle. NTN mRNA signals were also found in uterus and the oviduct. In testis, the transducing receptor RET as well as GDNF receptor α-1 (GFR)α-1 and GFRα-2 were distributed in complementary and overlapping patterns, the former at stages XI–XII–I and the latter at stages VII and VIII. GFRα-3 could not be detected. Expression of these trophic molecules suggests involvement of GDNF family ligands and related receptor components in reproduction.

Combating Parkinson's Disease--Step Three

Abstract: The degeneration of dopamine neurons in the nigrostriatal pathway of the brain results in the debilitating motor deficits of Parkinson's disease. In a Perspective, [Olson][1] discusses a new study ([ Kordower et al .][2]) demonstrating that injection of a lentiviral vector containing the gene encoding GDNF (a trophic factor for dopamine neurons) into the nigrostriatal pathway of monkeys with PD prevents neuronal loss and reverses some of the motor deficits of this disease. [1]: http://www.sciencemag.org/cgi/content/full/290/5492/721 [2]: http://www.sciencemag.org/cgi/content/short/290/5492/767