Diseases of the central nervous system (CNS) comprise a large variety of different pathological conditions. It is estimated that 35% of health burden measured as “disability-adjusted life years” is caused by CNS diseases. Many frequent CNS disorders develop on the basis of a genetic predisposition. An improved knowledge of the genetic basis and pathophysiology is the prerequisite for developing novel diagnostic and therapeutic tools for common CNS disorders.
The NeuroNet follows three major goals:
(i) to identify genes implicated in the etiology of genetically complex and common diseases of the CNS in human
(ii) to systematically explore molecular pathways associated with disease-related sequence variants by expression studies and identify novel target genes
(iii) to examine the pathophysiological mechanisms in model systems.
The NeuroNet comprises two major research areas (modules) with a total of five phenotypes (subnets):
(i) Neurodegenerative disorders: Alzheimer disease and Parkinson disease. The goal is to elucidate the genetic basis of these two age-dependent diseases and the biological function and the pathological role of the genes involved. This will be achieved by a close interaction of genetic, functional, and population-based studies.
(ii) Functional disorders: Affective disorder and psychosis, alcohol addiction and epilepsy. These diseases are characterized by episodic manifestations for which similar patho-mechanisms are responsible. In a highly integrated effort, studies in patients and cell/animal models will be performed.
Highlights of the NeuoNet achieved in the first funding period of the National Genome Research Network:
Alzheimer's disease: Variants of the genes of the plasminogen activator urokinase (PLAU) and the insulin degrading enzyme (IDE) both of which are involved in Aß degradation are associated with the disease.
Parkinson's disease: a) PARK8 was identified as a new gene responsible for another type of autosomal dominant Parkinson disease. b) Sporadic Parkinson disease is influenced by haplotypes in the ß-synuclein gene.
Affective disorder: Haplotypes around the locus of the D-amino acid oxidase activator gene (DAAOA, formerly G72) are associated with schizophrenia, bipolar and panic disorder, thus pointing to a shared etiology.
Epilepsy: a) It was shown that transgenic mice which conditionally express dominant-negative KCNQ2 subunits develop spontaneous seizures. b) Among 98 patients with idiopathic generalized epilepsy one patient with a de novo mutation in GABRA1 was identified and functionally characterized. c) In a large genome-wide linkage study with 561 STR markers four regions containing disease genes were identified.
Alcohol addiction: Mice with a mutated clock gene Period2 were shown to have an altered glutamatergic system resulting in a higher spontaneous alcohol intake than wild type mice.
Obesity has reached epidemic proportions in many countries. Its medical relevance is surpassing that of malnutrition on a world-wide scale. Approximately 20% of the German adult population is currently obese, defined by a BMI >30kg/m². Overweight (BMI = 25-30 kg/m²) and obesity represent a major risk factor for several common disorders including type 2 diabetes mellitus, cardiovascular disorders and cancer. As such, obesity represents one of the major challenges to health care systems.
Our major scientific aim is the identification of genes/alleles with an influence on body weight and their subsequent evaluation in clinical, epidemiological and functional terms. We anticipate that these alleles will either predispose to obesity or leanness. Whereas the elucidation of the molecular genetic mechanisms underlying obesity is the top priority due to the evident medical and epidemiological significance of this phenotype, we will also assess the relevance of detected alleles for co-morbid disorders and disorders associated with an aberrant weight regulation. Functional studies will focus on the implications of the detected genetic variation in appropriate in vitro and in vivo models.
The partners of our Network include key German centers for genetic research in appropriate animal models and humans. Large and well characterized samples including approximately 40.000 patients/probands are available including one of the worldwide largest trio samples (n=800) for childhood and adolescent obesity and epidemiological samples in total encompassing over 25.000 probands. The partners have an international reputation for the different scientific and clinical methodologies required for the successful functioning of an assembled research pipeline including e.g. high throughput genotyping, genetic biostatistics and epidemiology, bioinformatics, population genetics, mapping of quantitative trait loci (QTL) and identification of QTLs in rodents, gene expression profiling, pharmacology, nutritional sciences, diabetology, (preventive) cardiology, neuroendocrinology, neurology and psychiatric genetics.
Stroke is the third-most leading cause of death and the main cause of disabilities in Western societies, thus constituting a major socio-economic burden. In Europe, the U.S., and Japan, a combined number of 1.7 million people suffer from stroke each year. All efforts to treat stroke patients with compounds targeting early mechanisms of neuronal cell death (e.g. antioxidants or glutamate receptor blockers) have failed in the past, and new approaches to stroke therapy are urgently needed.
One avenue to new treatment should arise from understanding the molecular, cellular and systems processes underlying functional recovery from stroke, which are largely unexplored. In principle, the brain can achieve functional recovery from stroke by enhanced neuronal plasticity and by increased neurogenesis. Our network proposes to study these aspects in rodent models by harnessing new methodology, such as the Axaminer technology for cell type-specific profiling, combined with functional genomics at the transcript and proteome levels.
- Subproject 1 will investigate the roles of the two major NMDA receptor subtypes in forebrain in supporting functional recovery from defined unilateral photothrombotic cortical lesions in gene-targeted mice.
- Subproject 2 examines the genomic causes of the pro-recovery effects from photothrombotically induced stroke of voluntary or forced rehabilitation training, enhanced by EPO-related growth factors.
- Subproject 3 will examine the genomic repertoire responsible for the beneficial role of bone marrow stem cells in stroke.
- Subproject 4 investigates the important question of the genomic response evoked in adult neural stem cells by cerebral ischemia and enhanced by select growth factors.
- This study is complemented by Subproject 5, which employs a proteomic approach to examine the effect of neuroprotective factors (EPO) on adult neural stem cells and their survival after hypoxia.
