Investigation of the mechanism of CHMP2B-induced neurodegeneration using a novel transgenic mouse model

The neurodegenerative diseases, which include Alzheimer's disease, Parkinson's disease, Huntington's disease, motor neuron disease and prion diseases cause huge social and economic burden. This burden is set to increase dramatically as the population ages. Currently no therapies are available for these diseases, implying an urgent need to better understand their causes and develop therapies. We have identified a new gene, termed CHMP2B, that causes an inherited form of dementia. We have shown that CHMP2B affects the ability of cells to break down proteins, which is a problem that has been identified in many other neurodegenerative diseases. We therefore plan to further investigate how CHMP2B affects brain cells as this should give insight into pathways that could be targeted therapeutically in many neurodegenerative diseases. However, a major challenge for developing therapies is understanding why brain cells are specifically affected, so that directed therapies without side effects can be developed. In order to understand how CHMP2B specifically affects brain cells, we have generated mice that model dementia caused by CHMP2B. These mice are a very powerful model as they mimic the processes occurring in human CHMP2B dementia brains. They will therefore allow us to specifically examine brain cells at very early stages of the disease in order to identify why they are particularly vulnerable to dysfunction and death. Identification of these pathways should give insight into brain cell vulnerability in other neurodegenerative diseases and could identify new avenues for treatments.

The neurodegenerative diseases cause a devastating social and economic burden which will increase further as the population ages. No disease-modifying therapies are currently available, implying an urgent need to better understand neurodegenerative disease mechanisms in order to provide the foundation for therapeutic interventions. Mutations in the CHMP2B gene cause frontotemporal dementia, and affect two key cellular degradative pathways that converge on the lysosome: the endosome-lysosome pathway and autophagy. Both pathways have been implicated in a range of neurodegenerative diseases, suggesting that defining the mechanisms of CHMP2B-induced neurodegeneration will have broad impact for our understanding of neurodegenerative disease pathogenesis. However, how impairments in these central degradative pathways lead to selective neuronal dysfunction is unknown. This is a fundamental question as gaining insight into neuronal vulnerability is a key step for developing mechanism-based therapeutics. We have developed the first mouse model of CHMP2B-induced neurodegeneration, which recapitulates key aspects of human pathology. We will analyse endosomal and autophagic trafficking in primary neuronal cultures from these novel mice, in order to gain insight into the specific functions of these pathways that are required for neuronal survival. We will couple this analysis with state-of-the-art mass spectrometry to determine the specific proteins that accumulate due to impairments in these pathways. These insights should identify novel mechanisms that can be targeted therapeutically in a wide range of neurodegenerative diseases.

The aim of this proposal is to generate new knowledge about the mechanisms that lead to neurodegenerative diseases.

This knowledge will benefit the biotech/pharmaceutical industry by providing new leads for the development of therapeutics for neurodegenerative diseases. They may also benefit from our training of highly skilled researchers with the opportunity to transfer their skills to the biotech/pharmaceutical or related industries.

Dementia patients will ultimately benefit from the development of drugs that can slow or halt their disease; this would directly contribute to improving the health and well-being of society. The development and commercialisation of a dementia therapy would also lead to huge economic benefit.