Project ID NS-MH2024_60


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Department of Inflammation BiologyWebsite

Co Supervisor 1B Institute of Psychiatry, Psychology & Neuroscience, School of Neuroscience, Department of Basic & Clinical NeuroscienceWebsite

An aberrant innate immune response drives Parkinsonism and neurodegenerative synucleinopathy

Overview/Mission Statement:
This project aims to investigate the underlying mechanisms of neurodegeneration caused by the accumulation of alpha-synuclein (aSyn) in Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), and dementia with Lewy bodies (DLB). This independent research project will encompass a wide range of techniques in the fields of neuroscience and immunology – from stem cells to behavioural studies – and focuses on understanding the role of innate immune responses in the onset and progression of aSyn-related neurodegeneration.

The pathological hallmarks of synucleinopathies involve aSyn accumulation and aggregation in the cytoplasm and nucleus. Early events that trigger aSyn accumulation remain elusive, but recent studies suggest that abnormal activation of innate immune responses may play a role. Building upon these findings, we hypothesize that dysregulated immune responses contribute to disease initiation and progression, ultimately leading to aSyn-related neurodegeneration.

Rotation Project Objectives:
To explore if innate immune responses are activated at the initial phase of synucleinopathy. You will investigate alterations in expression of inflammatory target genes upon accumulation of aSyn using established model systems. The underlying pathogenic pathways will be elucidated using interaction studies.

Yearly Objectives:
Year 1: Training in Drosophila, cell culture and gene-editing. To study the effects of immune-related target genes on synucleinopathy using Drosophila and cell culture.
Year 2: Determine the role of immune signalling in established cell and animal models of aSyn proteinopathy.
Year 3: Continue objectives from year 2 while evaluating rare genetic variants in co-factors that regulate immunity using proteomics.

These studies will identify how innate immunity drives synucleinopathy and discover potential therapeutic candidates that can be clinically assessed for the treatment of these devastating, currently incurable diseases.

Lab Skills to be Acquired:
Drosophila husbandry; genetics; cell culture; electrophoresis; biochemistry; ELISA; Western blotting; immunohistochemistry; microscopy; flow cytometry; image analysis; bioinformatics; RNAseq and omics data analysis.

Representative Publications

Tummers B & Green DR. The evolution of regulated cell death pathways in animals and their evasion by pathogens. Physiol Rev, 2022 Jan 1;102(1):411-454. doi: 10.1152/physrev.00002.2021

Tummers B, Mari L, Guy CS, Heckmann BL, Rodriguez DA, Rühl S, Moretti J, Crawford JC, Fitzgerald P, Kanneganti TD, Janke LJ, Pelletier S, Blander JM, and Green DR. Caspase-8-dependent inflammatory responses are controlled by its adapter, FADD, and necroptosis. Immunity. 2020 June 16;52:1-13. doi: 10.1016/j.immuni.2020.04.010

Parsons RB, Kocinaj A, Ruiz Pulido G, Prendergast SA, Parsons AE, Facey PD, Hirth F (2022) Alpha-synucleinopathy reduces NMNAT3 protein levels and neurite formation that can be rescued by targeting the NAD+ pathway. Hum Mol Genet 31, 2918-2933. doi: 10.1093/hmg/ddac077.

Bridi JC, Bereczki E, Smith SK, Poças GM, Kottler B, Domingos PM, Elliott CJ, Aarsland D,Hirth F (2021) Presynaptic accumulation of ?-synuclein causes synaptopathy and progressive neurodegeneration in Drosophila. Brain Commun 3, fcab049. doi: 10.1093/braincomms/fcab049.

Bridi JC, Hirth F (2018) Mechanisms of ?-Synuclein Induced Synaptopathy in Parkinson’s Disease. Front Neurosci 12, 80. doi: 10.3389/fnins.2018.00080.