Brain neurogenesis through protein inhibition explored in search for new Parkinson’s disease treatment

A project aimed at stimulating adult brain repair by inhibiting the protein TRIM32 has received £809,457 of funding from the Dementia Consortium. MRC Technology and Professor Jens Schwamborn’s team at the Luxembourg Centre for Systems Biomedicine, University of Luxembourg, will explore a new treatment for neurodegenerative diseases like Parkinson’s, based on TRIM32 inhibition. Previous studies from this group have indicated that absence of TRIM32 leads to increased cell proliferation and reduced cell death.

Inhibition of TRIM32, a neuronal cell fate determinant, can stimulate adult neurogenesis which represents an innovative therapeutic approach towards endogenous brain repair. The Luxembourg team has already identified specific small molecule inhibitors directed against TRIM32, and the funding will allow them to prove the capability of neural stem cells for self-renewal.

Stem cells in the adult mammalian brain have the potential to generate new neurons and stimulate endogenous regeneration. Neurodegenerative conditions like Parkinson’s disease are associated with a reduction in stem cell activity, which decreases the ability to regenerate lost neurons.

The brain’s regenerative potential through activation of adult neurogenesis has been demonstrated in more acute degeneration, for example ischemia. Transient inhibition of stem cell differentiation would amplify the pool of available stem cells and allow production of more neurons. These neurons will replace the ones lost during degeneration.

In this project, small molecule inhibitors for TRIM32 will stimulate self-renewal and allow neuronal differentiation of endogenously present adult neural stem cells. Human induced pluripotent stem cells derived from Parkinson’s disease patients will be used to model the disease in vitro, and test the applicability of the small molecule for future drug development.

The background to the project originated from work carried out by Professor Schwamborn when he was based at the Institute of Molecular Biotechnology in Vienna, Austria and the work has been enabled through the development of a high throughput screening assay by the Lead Discovery Centre (LDC) in Dortmund, Germany.

The Dementia Consortium is a £4.5 million charity-industry partnership between Alzheimer’s Research UK, MRC Technology and pharmaceutical companies Abbvie, Astex, Eisai, Lilly and MSD. The partnership aims to bridge the gap between academic research and the pharmaceutical industry in the search for new drugs to slow neurodegenerative diseases.

Projects underway with funding from the Dementia Consortium:

  • University of Southampton: role of immune system protein CSF1R in blocking the inflammatory response to nerve cell death
  • International Centre for Genetic Engineering and Biotechnology (ICGEB): identify potential therapeutics to clear a misfolded protein forming aggregates in neurons of patients with Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar degeneration (FTLD)
  • The University of South Florida: explore the role of immune system regulator fractalkine in neurodegeneration.

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