Role of Cav1.2 and Cav1.3 Ca2+-channels for Parkinson´s disease: pathophysiology and targets for neuroprotection

Chronic diseases of the central nervous system (CNS) cause great suffering to afflicted individuals and a large burden on society. Depression, anxiety disorders, migraine and neurodegenerative diseases, such as Parkinson`s (PD) and Alzheimer`s disease (AD), occur with high and increasing prevalence but despite treatment improvements, their management is still unsatisfactory. As the molecular disease mechanisms are not fully understood, current drug therapies are mainly symptomatic and often cause side effects. An evident need towards advanced treatment options is to identify signaling pathways suitable for novel therapeutic strategies. Aim of this research network is to exploit our research experience with different well-validated disease models (PD, AD, Multiple System Atrophy, fear and anxiety disorders, depression) and selected patient cohorts and combine them with local basic research strengths to comprehensively study two signaling pathways that bear high potential for innovative therapeutic intervention: L-type Ca2+ channels (LTCCs) and epigenetic modulators, in particular histone deacetylases (HDACs). This was motivated by the fact that both pathways appear to participate in the etiology of several of these disorders, as well as by recent preliminary findings from our consortium suggesting that both signaling pathways can be (patho)physiologically linked to each other. Based on existing collaborations between network partners, we now systematically study the role of different LTCC isoforms in the etiology of PD, parkinsonism associated with Multiple System Atrophy, and AD. Our translational approach will range from the molecular level to in vivo studies, including electrophysiological investigations of the biophysical and pharmacological properties of different LTCC isoforms, their role in functional signaling networks in dopaminergic neurons in vital slices and in vivo studies in animal disease models to assess their potential significance as neuroprotective drug targets. For these and other CNS diseases we will also investigate the etiological role of epigenetic and, based on local expertise, non-coding RNA (ncRNA)-mediated mechanisms from various perspectives. This will involve identification of disease-relevant ncRNAs, biochemical properties of HDAC complexes in healthy and diseased brains and studying possible direct links between Ca2+ channel signaling and histone-modifying mechanisms. For example, we will study molecular mechanisms underlying disturbed fear memory regulation, in which both, LTCCs and epigenetic mechanism seem to be involved. This will include investigating the role of HDACs in studies with novel isoform-selective inhibitors. As both LTCC and HDAC signaling also affects neurogenesis, the molecular basis for this modulation will also be investigated in normal and diseased brain. Moreover, our efforts will also involve efforts to develop LTCC blockers with preferential CNS targeting as well as novel compounds interfering with isoform-selective HDAC activity or, as a novel concept, with protein binding to methylated DNA. Furthermore clinical investigations in our patient cohorts with Multiple System Atrophy and certain Ca2+ channel diseases (e.g. Familial Hemiplegic Migraine type 1) will be merged with insights from appropriate animal disease models to provide a translational strategy for developing disease biomarkers for progression and disease severity of these CNS disorders.