Molecular and cellular neurobiology
Molecular and cellular neurobiology
Neuronal membranes are mainly composed of phospholipids and these in turn form the physicochemical environment for membrane proteins such as receptors. In addition, neurotransmitters are present in phospholipid vesicles, so that release and reuptake are largely dependent on the intact arrangement of phospholipids. Finally, phospholipids and their fatty acid components themselves play a central role in many signalling systems of the cell.
Recent findings show that phospholipids are more abundant in CNS tissue after brain injury and degenerative brain diseases. The repulsive properties of these phospholipids could negatively influence regeneration. The regulation of phospholipid-induced signalling cascades, which among other things trigger retraction of neurites, could be a possible new starting point for therapeutic strategies after acute craniocerebral trauma, but also in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis. To date, we have no effective drugs and therapeutic strategies to cure neurodegenerative diseases. The current therapeutic interventions are too late in the neurodegenerative cascade, the process of degeneration can only be stopped with difficulty and even the rescue of the neurons that are still present cannot lead to a restitutio ad integrum. Here we need more detailed knowledge of the mechanisms that can lead to the regeneration of nerve fibres in order to be able to use targeted diagnostic biomarkers for the early detection of neurodegenerative disease, as well as to develop new therapeutic strategies to specifically intervene in the regulation of axonal outgrowth.
The Bräuer department has been working for several years on identifying molecular mechanisms during neuronal development and in de- and regeneration processes in the adult central and peripheral nervous system. Bräuer and colleagues identified a new brain-specific class of proteins, the LPPRs/PRGs (Strauss & Bräuer, 2013; Brindley & Bräuer, 2010; Bräuer & Nitsch, 2008). These are developmentally expressed and involved in remodelling processes in the CNS and PNS by modifying phospholipids or interfering with their signalling pathways (Coiro et al., 2014; Velmans et al., 2013, Trimbuch et al., 2009; Peeva et al., 2006; Savaskan et al., 2004). Data on the functional relevance of phospholipids point to a regulatory role in neuronal transmission (Trimbuch et al., 2009), the mechanisms of which are currently being elucidated. The temporal and spatial regulation of phospholipids is a sensitive process that essentially depends on lipid phosphatases, the phospholipid receptors and the autocrine motility factor ATX. Bräuer and colleagues were able to demonstrate ATX expression during development and in the adult brain in oligodendrocyte progenitor cells (Savaskan et al., 2007). Furthermore, upregulation of ATX has been demonstrated in reactive astrocytes after brain trauma (Savaskan et al., 2007). Since ATX hydrolyses lysophosphatidylcholine (LPC) to LPA, this protein expression suggests that increased LPA synthesis also occurs after brain injury.
Altered regulations of glycosphingolipid (GSL), specifically gangliosides, are associated with misfolding and aggregation of proteins associated with neurodegeneration. GSL refers to a group of lipids (called "sphingolipids") that are involved in the assembly of cell membranes. Gangliosides are mainly found in the cell membranes of cells of the central nervous system. There, via their carbohydrate group, they fulfil tasks in the interaction between individual cells, such as signal transmission. It is known that the abnormal accumulation of gangliosides plays a key role in the pathogenesis of various diseases, such as Sandhoff, Tay-Sachs and Gaucher disease. Ganglioside accumulation is also a common feature of seemingly quite different neurodegenerative diseases such as Niemann-Pick type C1 (NPC) and Alzheimer's disease (AD). NPC is a lysosomal lipid storage disease that is inherited in an autosomal recessive manner. In Germany, only about 500 - 700 cases of the disease are known (Vanier, 2010). Thus, this disease is one of the rare diseases. The mutation on the NPC1 gene leads to a cholesterol metabolism disorder which, via an unknown mechanism, leads to progressive neurodegeneration, especially of the Purkinje cells in the cerebellum. In addition to the deposition of cholesterol, there is also the deposition of glycosphingolipids, sphingomyelin, sphingosines and, especially in neurons, ganglioside accumulation. The disease always leads to death, as no curative therapy exists to date. Miglustat has been approved as a drug since 2009, but it only delays the disease. Beyond ganglioside accumulation, both diseases, NPC and AD, show the development of the same structural neuropathologies, such as oligomerisation and fibril formation of amyloid-ß and tau (Malnar et al., 2014). The importance of neuronal glycoshingolipid accumulation as a driving force of neurodegeneration was also shown in the identification of a genetic association between Parkinson's disease and Gaucher's disease (Sidransky et al., 2009).The influence of sphingolipid metabolism, its signalling pathway and the interplay of the proteins involved in it on neurodegeneration is currently still largely misunderstood. Previous studies in the AG Bräuer show that S1P receptor expression is altered in NPC-/- mice versus WT mice in qRT-PCR. These data will now be the starting point for further detailed molecular and cell biological studies, as well as the comparison of receptor expression in NPC mice versus AD mice. A focus will be on the study of S1P3 and S1P5, as our preliminary work shows an increase in S1P3 mRNA and a decrease in S1P5 mRNA expression in NPC-/- mice.
Neuropsychiatric developmental disorders, such as autism spectrum disorders or schizophrenia, are associated with abnormal dendritic spinous processes and synapse development. Unfortunately, little is known about the molecular mechanisms involved in both physiological and pathological formation of dendritic spinous processes. The aim of this project is to functionally analyse a new candidate, PRG5 (Plasticity Related Gene 5), which we have recently identified, in its role during dendritic spinous process development. Specifically, we aim to identify the molecular mechanisms and signalling pathways of PRG5 and to investigate newly discovered binding partners and their function in the process of brain ageing. We already know that endogenous PRG5 protein levels play a role in the correct development of dendritic spinous processes, their morphology and the stabilisation of excitatory synapses. In addition, we have shown that the C-terminus of PRG5 is involved in these mechanisms, probably through local lipid binding. Given that changes in spinous processes have been found in many different pathological processes, including neurodegenerative and neuropsychiatric diseases, PRG5 may be highly relevant in the susceptibility, pathology or therapy of such diseases. Our techniques combine the use of transgenic mouse models, primary nerve cell cultures and in vivo manipulations of different signalling pathways in mice by the in utero electroporation technique. This excellent combination of methods will allow us to identify new signalling pathways involved in brain development, not only for cellular processes or network functions, but also pathological changes in mouse behaviour, thereby providing a unified picture of how neuropsychiatric developmental disorders arise.