André Toulouse

Contributions of central and systemic inflammation to the pathophysiology of Parkinson's disease

Idiopathic Parkinsons disease (PD) represents a complex interaction between the inherent vulnerability of the nigrostriatal dopaminergic system, a possible genetic predisposition, and exposure to environmental toxins including inflammatory triggers. Evidence now suggests that chronic neuroinflammation is consistently associated with the pathophysiology of PD. Activation of microglia and increased levels of pro-inflammatory mediators such as TNF-α, IL-1β and IL-6, reactive oxygen species and eicosanoids has been reported after post-mortem analysis of the substantia nigra from PD patients and in animal models of PD. It is hypothesised that chronically activated microglia secrete high levels of pro-inflammatory mediators which damage neurons and further activate microglia, resulting in a feed forward cycle promoting further inflammation and neurodegeneration. Moreover, nigrostriatal dopaminergic neurons are more vulnerable to pro-inflammatory and oxidative mediators than other cell types because of their low intracellular glutathione concentration. Systemic inflammation has also been suggested to contribute to neurodegeneration in PD, as lymphocyte infiltration has been observed in brains of PD patients and in animal models of PD, substantiating the current theory of a fundamental role of inflammation in neurodegeneration. We will examine the current evidence in the literature which offers insight into the premise that both central and systemic inflammation may contribute to neurodegeneration in PD. We will discuss the emerging possibility of the use of diagnostic tools such as imaging technologies for PD patients. Finally, we will present the immunomodulatory therapeutic strategies that are now under investigation and in clinical trials as potential neuroprotective drugs for PD.

Progress in Parkinson's disease—Where do we stand? ☆

Parkinsons disease was first described in 1817 by James Parkinson. It is one of the most common neurodegenerative disorders, affecting the nigrostriatal pathways involved in the control of movement. Since the introduction of L-DOPA as a therapy in the mid-1960s, clinical management of the symptoms has progressed, but, at present, it remains impossible to stop the disease progression or to restore lost functions. A better understanding of neurodegeneration and of midbrain neuronal development has allowed the development of new pharmaceutical compounds with neuroprotective properties and has shown the potential of neurone replacement therapies in Parkinsons disease. Even though major obstacles remain before these can be transferred to the clinic, the progress made in the last 10 years brings hope of improved therapies for Parkinsons disease. In this paper we review the current knowledge of Parkinsons disease including its etiology, some of the current symptomatic therapeutic modalities, and recent progress in neuroprotective and cell replacement therapies.

Mutations in the nervous system–specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II

Hereditary sensory and autonomic neuropathy type II (HSANII) is an early-onset autosomal recessive disorder characterized by loss of perception to pain, touch, and heat due to a loss of peripheral sensory nerves. Mutations in hereditary sensory neuropathy type II (HSN2), a single-exon ORF originally identified in affected families in Quebec and Newfoundland, Canada, were found to cause HSANII. We report here that HSN2 is a nervous system-specific exon of the with-no-lysine(K)-1 (WNK1) gene. WNK1 mutations have previously been reported to cause pseudohypoaldosteronism type II but have not been studied in the nervous system. Given the high degree of conservation of WNK1 between mice and humans, we characterized the structure and expression patterns of this isoform in mice. Immunodetections indicated that this Wnk1/Hsn2 isoform was expressed in sensory components of the peripheral nervous system and CNS associated with relaying sensory and nociceptive signals, including satellite cells, Schwann cells, and sensory neurons. We also demonstrate that the novel protein product of Wnk1/Hsn2 was more abundant in sensory neurons than motor neurons. The characteristics of WNK1/HSN2 point to a possible role for this gene in the peripheral sensory perception deficits characterizing HSANII.

Parkinson's disease in the nuclear age of neuroinflammation

Chronic neuroinflammation is associated with the pathophysiology of Parkinsons disease, a movement disorder characterised by deterioration of the nigrostriatal system of the brain. Recent studies have yielded important insights into the regulation of inflammation by nuclear receptors, a superfamily of ligand-activated transcription factors. Certain nuclear receptors are also emerging as regulators of neurodegeneration, including the degeneration of dopaminergic neurons in Parkinsons disease, and the importance of transcriptional control in this process is becoming increasingly apparent. Here, we discuss the role of Nurr1, peroxisome proliferator-activated receptors (PPARs), retinoic acid receptors, and glucocorticoid receptors in neuroinflammatory processes that contribute to dopaminergic neuronal degeneration. We examine current evidence providing insight into the potential of these important players as therapeutic targets for Parkinsons disease.

Neurotrophic factors for the treatment of Parkinson's disease

Parkinsons disease (PD) is a common neurodegenerative disorder caused by the progressive degeneration of the nigrostriatal dopaminergic pathway. The resulting loss of dopamine neurotransmission is responsible for the symptoms of the disease. Available treatments are initially successful in treating PD symptoms; however, their long-term use is associated with complications and they cannot stop the neurodegeneration. Current research aims at developing new therapies to halt/reverse the neurodegenerative process, rather than treating symptoms. Neurotrophic factors are proteins critical for maintenance and protection of neurones in the developing and adult brain. Several neurotrophic factors have been investigated for their protective effects on dopaminergic neurones. Here we review some of the most promising factors and provide an update on their status in clinical trials.

DRD3 and DAT1 genes in schizophrenia: an association study.

OBJECTIVE To investigate the role of the dopamine receptor 3 (DRD3) and transporter 1 (DAT1) genes in schizophrenia or in modulating its phenotype. METHODS a Ser9Gly polymorphism in codon 9 of the DRD3 and a VNTR polymorphism in the DAT1genes were examined in two groups of schizophrenic patients, one of excellent neuroleptic responders (N=42) and one of nonresponders (N=64). A group of healthy volunteers screened for major psychiatric disorders was also included (N=89). In addition, age at onset of psychotic symptoms, attention performance and family loading for schizophrenia spectrum disorders were compared between patients with different genotypes in the DRD3 and DAT1 genes. RESULTS No significant differences in the allelic distribution of the DRD3 and DAT1 polymorphisms were detected between schizophrenic patients and controls. A trend toward an excess of DRD3 genotype Gly/Gly was observed in neuroleptic nonresponder schizophrenic patients compared to controls (chi(2)=3. 30, df=1, p=0.07). No significant differences in age at onset of psychotic symptoms, attention task performance or family loading for schizophrenia spectrum disorders were observed between groups with different DRD3 and DAT1 genotypes. CONCLUSION These results do not support the role of either of these genes in increasing susceptibility to schizophrenia or in modulating its phenotype in the studied population.

Molecular cloning and characterization of human RAI1, a gene associated with schizophrenia

Schizophrenia is a common neuropsychiatric disorder of uncertain etiology that is believed to result from the interaction of environmental factors and multiple genes. To identify new genes predisposing to schizophrenia, numerous groups have focused on CAG-repeat-containing genes. We previously reported a CAG repeat polymorphism that was shown to be associated with both the severity of the phenotype and the response to medication in schizophrenic patients. In this article, we now report the genomic structure of this gene, the retinoic acid inducible-1 gene (RAI1), and present its characterization. This gene, located on chromosome 17p11.2, comprises six exons coding for a 7.6-kb mRNA. The RAI1 gene is highly homologous to its mouse counterpart and it is expressed at high levels mainly in neuronal tissues.

Transgenic expression of an expanded (GCG)13 repeat PABPN1 leads to weakness and coordination defects in mice.

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder caused by a (GCG)n trinucleotide repeat expansion in the poly(A) binding protein nuclear-1 (PABPN1) gene, which in turn leads to an expanded polyalanine tract in the protein. We generated transgenic mice expressing either the wild type or the expanded form of human PABPN1, and transgenic animals with the expanded form showed clear signs of abnormal limb clasping, muscle weakness, coordination deficits, and peripheral nerves alterations. Analysis of mitotic and postmitotic tissues in those transgenic animals revealed ubiquitinated PABPN1-positive intranuclear inclusions (INIs) in neuronal cells. This latter observation led us to test and confirm the presence of similar INIs in postmortem brain sections from an OPMD patient. Our results indicate that expanded PABPN1, presumably via the toxic effects of its polyalanine tract, can lead to inclusion formation and neurodegeneration in both the mouse and the human.

Analysis of 14 CAG repeat-containing genes in schizophrenia.

Recently, it has been suggested that trinucleotide repeat-containing genes may be involved in the etiology of schizophrenia. This study was aimed at investigating putative associations between allelic variants or expansions of CAG repeat-containing genes (CAGrCG) and schizophrenia or its variability with respect to responsiveness to conventional neuroleptics. CAG repeat allelic variants of 14 expressed sequences were compared among three groups of subjects: neuroleptic-responder (R; n = 43) and neuroleptic-nonresponder (NR; n = 63) schizophrenic patients, and a control group (C; n = 122). No CAG expansions, in the range of those observed in neurodegenerative diseases, were identified in these 14 expressed sequences. The sizes of CAG repeat for the hGT1 gene were marginally different among the three groups of subjects (Kruskal-Wallis H (2, 456) = 10.48, Bonferroni corrected P = 0.047). Comparisons among the different groups indicated that neuroleptic responders have shorter alleles compared to controls (Mann-Whitney adjusted Z = -3.23, P = 0.0012). NR patients were not different from controls. These preliminary results suggest that the hGT1 gene, or a gene in its vicinity, may be involved in the etiology of schizophrenia or in modifying the disease phenotype with regard to outcome and/or neuroleptic responsiveness. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:694-699, 1999.

Interleukin-1β contributes to dopaminergic neuronal death induced by lipopolysaccharide-stimulated rat glia in vitro

Inflammation is involved in the pathology of Parkinsons disease, a disorder characterised by degeneration of dopaminergic neurons. This study demonstrates that conditioned medium (CM) from lipopolysaccharide (LPS)-treated rat glial-enriched cortical cultures induced death of embryonic rat dopaminergic neurons in vitro, an effect which was additive to the toxicity of the neurotoxin 6-hydroxydopamine. Interleukin-1β (IL-1β) in the CM may mediate this neuronal death. IL-1R1 was found to be expressed on dopaminergic neurons. Blockade of IL-1R1 prevented CM-induced dopaminergic neuronal death. This study suggests that IL-1β in CM from LPS-stimulated glia contributes to dopaminergic neuronal death induced by glia-conditioned medium.