SITAU

siRNA-based therapy for cerebral tauopathies

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 Obiettivo del progetto (Objective)

'Neurodegenerative disorders are an increasing healthcare problem. Many of these diseases are characterized by aggregation of proteins, which leads to neuronal dysregulation and cell death. Neurofibrillary tangles, pathological aggregates of tau protein, are the characteristic neuropathological stigmata defining a group of disorders termed Tauopathies. In Frontotemporal Dementias with Parkinsonism linked to Chromosome 17 (FTDP-17), mutations in the tau gene have been identified as cause of the disease. Mice expressing FTDP-17-mutant tau protein develop age-related accumulations of neurofibrillary tangles, behavioural impairments and neuronal cell loss, similar to patients with FTDP-17. When the expression of such mutant tau protein was suppressed by means of a tetracycline-controlled expression system in mice with advanced pathology, cognitive deficits were reversed and neuronal loss was prevented. We therefore propose to study if the small inference RNA (siRNA) technique can be instrumentalized in transgenic mice overexpressing human wild-type or mutant tau (R406/P301S) to suppress tau-gene expression, neuronal cell loss and behavioural deficits. To achieve widespread distribution of siRNA in the brain, a polyethyleneimine delivery system with intracerebroventricular administration will be used, which technique has a good chance to qualify for clinical application. We believe that this project will significantly advance the research in tau-related pathologies.'

Introduzione (Teaser)

Tauopathies are a group of neurodegenerative disorders marked by an accumulation of proteins. These are termed neurofibrillary tangles and result in neuronal losses and cell death.

Descrizione progetto (Article)

Unhealthy aggregates of tau proteins are the main characteristic of tauopathies. Mutations in Tau genes are charged with causing frontotemporal dementias with parkinsonism linked to chromosome 17 (FTDP-17).

In research using a mouse model, experiments with FTDP-17-mutant tau proteins displayed similarities to patients with FTDP-17. That is, the mice also developed age-related aggregates of neurofibrillary tangles, behavioural disabilities and neuronal cell loss.

In previous research, when expression of the mutant proteins was suppressed at an advanced stage, cognitive deficits were reversed and neuronal loss was halted. Therefore, the 'siRNA-based therapy for cerebral tauopathies' (SITAU) project set out to study if the small interference RNA (siRNA) technique can be used in transgenic mice to smother tau gene expression, behavioural impairments and neuronal cell loss.

In order to deliver the siRNA to cells, several techniques and transfection agents were tested with varying results. siRNA, essential to all forms of life, plays a role in encoding genetic information and can be directed to interfere with the expression of a specific gene.

Here, SITAU project partners investigated in vivo siRNA delivery of the transfection agents polyethyleneImine(PEI-)-based and Accell-siRNA to evaluate interference efficacy. The results showed this approach was neither effective nor toxic.

In studies using Lipofectamine 2000 as a transfection agent, researchers were not able to produce any reliable and consistent reduction in the expression (knockdown) of the proteins. However, experiments with Accell-siRNA, which has been modified to enter cells without a transfection agent, showed that two proteins, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and cyclophilin B (CycloB), could be effectively knocked down.

The project's outcome is a significant step towards examining the effect of siRNA interference in a clinical model of human tau-related disease. Also, more experiments on an animal model will ultimately reveal how siRNA interference can be applied as a treatment strategy for tauopathies and related disorders.