Use of “omic” approaches for the study of the pathogenetic mechanisms underlying neurodegenerative and neurodevelopmental diseases, to search biomarkers and molecular targets useful in the prognosis and to develop drug therapies
Dr Tiziana Bachetti
Background
Neurodegenerative and neurodevelopmental diseases, whose etiology can be either predominantly genetic, or non-genetic or multifactorial, group a vast number of disorders that often share molecular alterations resulting in irreversible damage at the neuronal level. In support of this consideration is the observation that the death of neurons can be the result of malfunctioning neuronal proteins that cause toxicity in the neuron itself or in other cells of the nervous system such as astrocytes, oligodendrocytes and microglia. The importance of crosstalk between the neuronal and glial cellular components of the nervous system is now well defined, in order to maintain a functional homeostasis that regulates the myelination of the axon and a correct turnover of neurotransmitters, thus allowing the transmission of nerve impulse along the axon and communication at the synapse level occur correctly. To date, cellular models and animal models of vertebrates, such as zebrafish, have made it possible to characterize pathways involved in the onset and progression of these pathologies, essential elements for identifying and validating therapeutic targets in order to develop targeted approaches to the search for specific drugs. In particular, thanks to the transparency during the first days of embryonic life and the speed of the reproduction cycle, zebrafish is a widely used model for functional studies of fluorescent fusion proteins which can thus be expressed easily visualized and followed during stages of development, growth and aging.
In addition, molecular genetics approaches have been used to unravel in cis and in trans elements acting as modifier of neurodegenerative phenotypes, thus revealing very useful to provide information suitable for molecular diagnosis and also for prognosis.
Hypothesis and significance
Latest generation “omic” approaches, such as transcriptomics and differential proteomics, applied to cellular and animal models, have made it possible to acquire large-scale information on dysregulated pathways in various pathologies of the nervous system, highlighting differences and similarities that are fundamental for knowledge and the identification of drug targets, necessary to develop specific therapies for this broad class of diseases. In particular, proteomics, thanks to its versatility of applications and use, has proved to be an approach of fundamental importance for the characterization of over- or under-expressed proteins in pathways involved in the maintenance of neuronal homeostasis.
In addition to other molecular biology approaches, omics studies will be considered as a tool to improve our knowledge on the molecular basis of neurodegeneration. Starting from cellular and zebrafish models characterized by altered astrocytes function due to compromised cytoskeletal conformation, results achieved on regulation of gene and protein expression will be analyzed for their consistency with pathways involved in neurodegeneration.
Significance and Innovation
The main innovation will be provided by the following items:
- Use of MALDI-imaging approach allowing to perform mass spectrometry analysis in situ in tissue; the great advantage is that this method is label-free and allows multiplex analysis of hundreds to thousands of molecules in the very same tissue section simultaneously. As the investigation of morphological and molecular tissue features is the basis of generating knowledge about clinicopathological entities, diagnostics, prediction, and prognosis, the possibility of achieving a number of information in a brief time is the solution to the challenge for clinicians of the time needed to give a report.
- Investigation of elements modifier the neurodegenerative phenotype will increase the knowledge on mechanisms underlying neurodegeneration and it is an approach that could be moved to other diseases characterized by variable expressivity.
- Overall, the combination of classical molecular biology and “omics” approaches will join past and future technologies applied to research in medicine in order to improve the outcome of results.
Translational relevance and impact for the National Health System (SSN)
Due to the general demographic aging of the population, the neurodegenerative diseases produce a significant impact on health public, both in terms of specific cost for the diagnostic-clinical course of the patient, both for the different repercussions on the social network that surrounds him. Frequently they cannot be cured or significantly slowed and the final outcome is death. Currently, for many neurodegenerative diseases, there are no specific therapies, but only assistance; therefore, it is desirable to have specific and efficient drugs, the development of which cannot be the sole responsibility of pharmaceutical companies but requires investment in research.
Moreover, prognosis of neurodegenerative disease is often a challenge for clinicians. The integration of the results obtained with information derived from studies on different models, animals and cellular, will allow to expand the knowledge on the basic mechanisms and to be able to transfer this knowledge in the pharmaceutical field, for the development of therapies alternative or as adjuvants to symptomatic treatments, and to clinics, to improve the knowledge available to help clinicians during the prediction of disease prognosis.
