Proteinopathies Modelling Group Centre for Preclinical Testing

The normal function of synucleins in synaptic transmission and in the development of dopaminergic neurons in the midbrain. Proteins in pathological processes: cytotoxicity of alpha-synuclein aggregation intermediates, toxic enhancement of synuclein function in neurons and its role in motor neuron disease, age-dependent depletion of functional synucleins from neuronal synapses and its contribution to impaired neurotransmission. These studies are being conducted on various synuclein knockout mice and mouse lines for conditional knockout of the alpha-synuclein coding gene with tamoxifen-induced pan-neuronal inactivation to study the effects of adult and embryonic alpha-synuclein depletion in the nigrostriatal system.

Creation and maintenance of in vivo models reproducing key links in the pathogenesis of human neurodegenerative diseases, which are characterized by impaired metabolism and function of certain proteins with an increased tendency to aggregation. Using models for reproducible testing of therapeutic approaches to the treatment and prevention of neurodegenerative proteinopathies

A significant number of ALS-associated mutations has been identified in genes encoding RNA-binding proteins. Moreover, some of these proteins possess prion-like domains that are responsible for their high propensity to aggregate. Consistently, pathological aggregates formed by these proteins were found in the nervous system of both familial and sporadic ALS and certain other neurodegenerative diseases. To clarify this, we currently employ various cell and animal models to study FUS, one of RNA-binding proteins involved in pathogenesis of ALS and related diseases.

Intracellular and extracellular accumulation of fibrillary proteins, beta-amyloid and hyperphosphorylated Tau, in patients with Alzheimer’s disease (AD) leads to chronic and progressive neurodegenerative process. Overaccumulation of aggregates results in synaptic dysfunction and inevitable neuronal loss. Although the exact molecular pathways of the AD still require better understanding, it is clear this neuropathology is a multifactorial disorder. We focused on design of multitargeted drugs acting on multiple key molecular pathways and provides a promising strategy for pre-clinical trials on our transgenic 5xFAD, APPswe/PS1dE9, TauP301S mice models.