LE STUDIUM / Marie Skłodowska-Curie Research Fellow
In residence at
Prof. Patrick Vourch'
Protein translation enhancement therapy for the treatment of neurodegenerative diseases
Neurodegenerative diseases are characterized by degeneration of neurons in the brain affecting millions of people worldwide. Synaptic dysfunction has been noted as one of the earliest hallmarks, occurring in advance of neuronal death in Alzheimer disease (AD), which is the most common type of neurodegenerative diseases, and in second place Amyotrophic lateral sclerosis (ALS). Both AD and ALS show similar synapse pathology due to a decrease of the synaptic vesicles proteins (i.e.
synaptophysin and synapsin 1) affecting synapses, which is essential for transmitting, processing and storing information. Currently there is not cure for both neurodegenerative disorders, current treatments remains palliative and no therapy exists which approaches the root cause of the condition. Reduction of synaptic transmission in AD and ALS is caused by progressive down regulation of many synaptic genes affecting synapses, thus I propose that introduction of specific RNA enhancement (RNAe) constructs targeting down regulated mRNA transcripts of synaptic genes to enhance protein translation and synapses as a consequence may help to revert the disease phenotype. My long-term goal is to use RNAe to develop a gene therapy for patients with neurodegenerative disorders, specifically AD and ALS. My central hypothesis is that stabilization of synaptic genes’ mRNAs by RNAe will be effective in enhancing the levels of the targeted proteins that are down-regulated. To investigate, we will pursue the following specific aims: In Aim 1, we will carry out in vitro studies in cell line’s models to select specific RNAe constructs that will lead to translation enhancement and normalize the protein levels of down regulated synaptic genes (synaptophysin and synapsin 1). In Aim 2, we will utilize selected RNAe constructs from Aim 1 to carry out preclinical in vivo studies in transgenic mouse models. Transgenic mice will be treated at the early stages of AD and ALS during several months. We will follow behavioral performances every weeks, and at the end of the treatment we will assess disease phenotype and disease biomarkers. We will also address a possible toxic effect caused by the therapeutic RNAe constructs. The outcome of this work will lead to development of a therapy to prevent and treat neurodegenerative diseases such as AD and ALS.