Preclinical projects It is thought that the presence of alpha-synuclein protein clumps in nerve endings in the brain is an early event in the development of Parkinson’s (PD). The presence of these clumps is associated with a reduction in the release of dopamine from the nerve cells (neurons) and this causes an alteration in communication between neurons - reflected in the development of symptoms of Parkinson's. Understanding brain insulin resistance and Parkinson’s - Dr Konrad Talbot - There is evidence that many early factors in PD, including alpha-synuclein clumping, can induce brain insulin resistance, which can in turn cause or exacerbate many other aspects of the disorder. This might explain why a clinical trial of an anti-diabetic drug known to reduce brain insulin resistance (exendin-4) produced evidence not only of symptomatic relief, but of slowing disease progression. Given the urgency of finding ways to slow what is today the inexorable decline of patients with PD into disability, the proposal study addressed issues related to the role of brain insulin resistance in PD and preclinical issues in the choice of anti-diabetics to treat it. Recent newer members of this drug class have been found to be more effective than exendin-4 in reducing brain insulin resistance. Dr Talbot is testing the magnitude of brain insulin resistance in PD, to determine which anti-diabetics are most effective in reducing insulin resistance, and to identify likely causes. Testing the neuroprotective effects of novel long-lasting incretin hormone analogues in models of Parkinson’s - Christian Holscher, Lancaster University - Drugs originally developed as treatments for type 2 diabetes have been shown to have protective properties in the brain in several animal models of disease. In animal models of PD, exendin-4, has shown impressive protective effects, and a recent clinical trial (CPT funded research) that tested this drug in patients with PD also found very promising protective effects. Professor Holscher and colleagues have now developed a range of novel drugs that have superior properties compared with exendin-4. They are longer lasting and do not induce an immune response in the way exendin-4 does - these drugs are modelled on human gut hormones. Exendin-4 also has the disadvantage of lasting only a few hours in the blood stream. The new peptide drugs have been tested in a range of neurotoxicity assays and have shown powerful effects. In addition, Professor Holscher has tested a novel long-lasting peptide drug that has been developed by Professor Stephen Bloom as a new treatment for diabetes. This drug showed impressive neuroprotective effects in a pilot study. Professor Holscher has tested several of these new drugs in standard models of PD, in comparison with exendin-4 to assess whether the novel drugs have superior neuroprotective properties. Nurturing growth factors with Nurr1- Professor Anders Bjorklund, Lund University, Sweden - Nurr1 was originally discovered as an important growth factor in young brain development that differentiated and promoted successful growth of midbrain dopamine neurons. However, recent studies, funded by CPT, have shown that Nurr1 plays an important role in the adult brain too and there is evidence that impaired Nurr1 in neurons is a feature of Parkinson's (PD). There is also a correlation between too little Nurr1 production and too much of the toxic alpha-synuclein which spreads throughout neurons in PD, which in turn blocks the naturally occurring growth hormone GDNF in the brain. The goal of this project is to test a new orally available Nurr1 activating drug (an agonist) to see if it is neuroprotective and disease modifying in models of PD. Mitochondria are organelles which are found in every cell of the human body except red blood cells and they convert the energy of food molecules into the ATP which is used to power most cell functions. If mitochondria become diseased, they cannot carry out their critical function. Many diseases of aging are caused by defects in mitochondrial function, including Parkinson's. Investigating the mode of action of MSDC-0160 - Professor Patrik Brundin, Van Andel Research Insititute - Professor Brundin is exploring whether a novel type-2 diabetes drug (MSDC-0160) adapts mitochondrial function to see if this will be neuroprotective in two different models of Parkinson’s. He is using two different models to clearly show how this drug works. Professor Brundin aims to prove that MSDC-0160 improves mitochondrial activity and stops the degenerative pathways associated with PD (preventing alpha synuclein aggregation). We expect to see the results of his work soon with the hope that we can progress this compound towards more extensive trials. Mitochondrial piRNAs: Role in PD Pathogenesis and Novel Targets for Therapeutic Intervention - Professor Matthew Wood and Sabrina M. Heman-Ackah (researcher) - Oxford University - Using induced pluripotent stem cells (iPSCs - which are patient-derived skin cells that have been reprogrammed to become dopamine neurons) and treating these neurons with PD-causing toxins, we have identified a new class of small non-coding RNAs, not previously linked to Parkinson’s. Small non-coding RNAs have wide and varied biological functions in health and disease and are essential for brain development and cognition. Dr Wood’s team has identified two small non-coding RNAs, previously annotated as microRNAs (miR-1974 and miR-1978), that may in fact be piRNAs. Importantly, until now only miRNAs have been well characterised to play roles in the development of PD, no such role has been previously described for piRNAs. The discovery that piRNAs may mediate cell response to dopaminergic neurotoxins represents a novel avenue for the development of disease-modifying therapeutic interventions and finding a biomarker for Parkinson’s. Click here to download more information of this trial. Preclinical evaluation of D-PUFAs (fatty acids) as a therapeutic intervention for PD - two linked projects, by Professor Patrik Brundin, VARI, Grand Rapids, US and Professor Flint Beal, Weill Cornell Medical College, US - Investigating whether these essential fatty acids (D-PUFA's) might modify the pathology of PD in complimentary animal models in preparation for a large scale clinical trial. Oxidative stress has been linked with the death of neurons in PD. Professors Patrik Brundin and Flint Beal are working on interlinked proposals to investigate whether a very safe dietary supplement with essential fatty acids that are reinforced at the molecular level to prevent cell damage through oxidative stress might be beneficial in Parkinson’s. This work is just getting underway. To clinically evaluate this therapeutic strategy in PD patients the aim is to: Define the effect of D-PUFAs (administered as a dietary supplement) in an animal model exhibiting specific nerve cell death akin to that seen in PD. Importantly this will complement the studies in neurotoxin-based PD models, which poorly recapitulate PD neuropathology. Study whether blocking oxidative damage to lipids by supplementing with non-oxidatable fatty acids in the diet will also protect against toxicity mediated by a virally delivered human A53T alpha-synuclein delivered to the substantia nigra in an animal model. Optimise the administration of D-PUFAs and determine the levels of drug exposure and protection in relevant brain regions, and develop biomarkers of drug (D-PUFA) exposure, essential for choosing dosages in clinical trials.