Discoveries

Before the ASAP initiative, PD research primarily centered on mechanisms involving known risk genes (e.g., alpha-synuclein, LRRK2, GBA1, PRKN, PINK1) and disrupted pathogenic processes like mitophagy, lysosomal/lipid pathways, immune responses, and proteostasis. As genetic advancements over the past decade have shifted focus from single genes to broader genomic changes, there is a greater need to better understand the effects of PD risk genes on cellular and organelle function within the context of these disrupted pathogenic processes.

The 14 teams funded under the PD Functional Genomics theme use innovative approaches to uncover mechanisms contributing to PD pathogenesis and progression. The research focuses on two areas:

• Conducting unbiased analyses of human datasets and models to identify novel targets and mechanisms.
• Investigating the functional impact of known risk genes (e.g., SNCA, GBA, LRRK2, PRKN, PINK1) and pathogenic pathways (e.g., mitophagy, lysosomal dysregulation) on disease progression and heterogeneity.

ASAP CRN teams have:

• Identified several promising druggable targets for PD by conducting unbiased analyses of human datasets and models by understanding genetic influences on PD pathogenesis and progression, uncovering new therapeutic opportunities.
• Significantly advanced our understanding of how known genetic targets and their downstream pathways contribute to PD pathology and progression.

Learn more about the teams collaborating under the PD Functional Genomics theme.

Before the ASAP initiative, growing evidence suggested the immune system’s involvement in PD based on studies observing activated immune cells in post-mortem brain tissues and circulating biofluids of PD patients. Clinical and genetic links between autoimmune conditions, such as Crohn’s disease and PD, were emerging, with initial evaluations of targets and processes in cellular and animal models. However, gaps remained, including the lack of a clear mechanism connecting the immune system to PD, uncertainty about whether immune changes were a cause or consequence of the disease and limited understanding of the timing and role of innate and adaptive immune responses in PD progression.

To address these gaps, seven teams under the Neuro-Immune Interactions theme:

• Investigated the roles of immune cells in both the central nervous system and the periphery in PD development and progression. 
• Studied the gut’s role in mediating PD progression through inflammatory pathways in collaboration with teams exploring circuitry and brain-body interactions, expanding the understanding of neuro-immune pathways in PD.

These teams have:

• Researched the role of the gut in activating neuroinflammation, highlighting the complex interplay between gut dysfunction, immune activation, and PD pathology.
• Explored the role of PD-linked genes in immune changes, underscoring the involvement of PD-linked genes in immune regulation and emphasizing the importance of continued study of PD within the immune system’s context.
• Identified the multifaceted role of immune cells involved in PD, underscoring the interplay between peripheral and central immune systems and their contributions to neuroinflammation, neurodegeneration, and disease progression.

Explore the teams collaborating under the Neuro-Immune Interactions theme.

Dopamine degeneration in the substantia nigra, a hallmark of PD, disrupts brain circuitry in the basal ganglia. Despite advances in understanding the role of these regions in PD symptomology, the role of many brain regions and cell-types remain unclear. Additionally, how peripheral systems – like the gut, immune system, and autonomic nervous system – interact with the brain to influence disease onset and progression remains an open question. 

Over three years, 14 ASAP teams studied brain-body interactions, cortical and basal ganglia circuits, and critical cell types, leading to the novel findings.

These teams have:

• Identified markers for vulnerable and resilient dopamine neuron subpopulations in PD, which is critically important for the development of targeted treatment options.
• Uncovered insights into striatal subpopulations and levodopa-induced dyskinesia (LID), highlighting potential therapeutic strategies to alleviate LID and improve the quality of life for PD patients undergoing long-term levodopa therapy.
• Provided insights into alpha-synuclein in PD circuits and its impact on neuronal function.

Find out about the teams collaborating under the Circuitry and Brain-Body Interactions theme.