Developing a mechanistic rationale for alpha-synuclein targeting therapies in Parkinson's disease

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Parkinson's disease is the second most common neurodegenerative disease affecting ~1% of the population over the age of 60. Currently there are only partial symptomatic therapies and no cure. It primarily affects movement and posture due to the death of dopamine producing nerve cells. Mood, memory decline and other difficulties also become prominent as the disease progresses with a significant impact on the quality of patients' and carers' lives. At the molecular level, Parkinson's disease is caused by the accumulation of a small protein called alpha-synuclein and its conversion into clumps called aggregates inside vulnerable neurons. The aggregation of alpha-synuclein causes the death of neurons. Why some types of neurons such as the dopamine producing cells, are more vulnerable to this process of alpha-synuclein aggregation is not fully understood. This may relate to their inability to clear aggregates, counteract their damaging effects or communicate with other types of resident brain cells that survey the environment for toxins such as microglia. One of the limitations for progress has been the lack of human models that recapitulate such pathological events. We have used stem cells derived from patients to generate dopamine producing neurons and triggered alpha-synuclein aggregation in a way that mimics aggregates found in Parkinson's brain. Formation of such aggregates inside the human neurons developed over a period of weeks and caused their death. In this model we have observed that removal of alpha-synuclein aggregates is enhanced when microglia, also derived from stem cells are in contact with neurons. Because we can recapitulate in a human model two critical events of the disease (aggregation and nerve cell death), we are ideally positioned to investigate important outstanding questions in Parkinson's research. (i) Can neurons clear aggregates? We have used state of the art genetic tools (CRISPR) to interrogate all relevant pathways in an unbiased fashion. We have identified a factor that tags alpha-synuclein aggregates for destruction and we will determine how this occurs inside nerve cells. We will employ light-sensitive tags in living neurons to fully understand how the destruction of alpha-synuclein in neurons changes when it is converted from non-aggregated to an aggregated form. (ii) Are neurons with aggregates influenced by external signals from other brain cells? In the brain, neurons respond to or process aggregates in communication with surrounding cells such as microglia. How such signals influence neurons is unclear and complicated by the fact that human microglia often respond differently from what is observed in commonly used mouse models. We will use our human models to understand how microglia promote the removal of aggregates from neurons by testing their ability to "eat up" damaged parts of neurons with aggregates or take up and degrade aggregates released by neurons. We will also analyse which genes are expressed in each microglial cell and neuron individually, to define signals that are responsible for the beneficial interactions we observed. (iii) What makes dopamine producing neurons vulnerable to aggregate-induced death? We will combine our genetic tools (CRISPR) and human models to interrogate factors identified by our gene expression studies. In this way we will identify novel ways to stop the toxic effects of alpha-synuclein aggregation. We will test whether these factors are also detected in Parkinson's brain and are reduced in vulnerable brain regions. Through a multifaceted investigation of a human model of alpha-synuclein aggregation, we aim to understand critical events that cause Parkinson's disease and develop novel therapeutic approaches.