Title: Defining nanoscopic structure-function relationship of α-Synuclein aggregates in neurodegenerative disorders
Funder: The Academy of Medical Sciences

Abstract: This study hypothesises that the clinical and pathologic features of each synucleinopathy disorder is encoded by a distinct conformation of the aggregated α-synuclein (αSyn). Synucleinopathies, a subgroup of neurodegenerative diseases, are characterised by the deposition of αSyn aggregates in the central nervous system (CNS). Most prevalent synucleinopathies are Parkinson’s disease (PD), Dementia with Lewy bodies (DLB), Multiple System Atrophy (MSA). Although αSyn deposition is observed in all of the synucleinopathies, it is not known why the same protein αSyn spread with distinct spatiotemporal patterns in the CNS for different synucleinopathies, targets different types of cell populations and ultimately leads to a spectrum of diseases with distinct clinical symptoms and variable rates of disease progression. To explain this apparent paradox, I hypothesise that the molecular mechanism of αSyn aggregation is distinct for different synucleinopathies, and the structural and functional properties of aggregates generated in this aggregation are different. To test this hypothesis, I will isolate αSyn aggregates from the postmortem of each synucleinopathy patients and recapitulate cell-type-specific seed-induced aggregation and spread in patient-derived cellular models. Skin fibroblasts of synucleinopathy patients will be used to derive Neural Progenitor Cells, and these progenitor cells subsequently will be differentiated into distinct neurons and glial cells to mimic the CNS environment of each disease. Using super-resolution based imaging, I will determine the structural and compositional features of individual αSyn species which form along the aggregation pathway and elucidate how these molecular structural and compositional features underpin the unique pathological abnormalities in PD, DLB and MSA.

Lay abstract: Parkinson’s disease (PD), Dementia with Lewy bodies (DLB) and, Multiple System Atrophy (MSA) are a group of neurodegenerative disease which are characterised by the deposition of a protein called α-synuclein in the central nervous systems (CNS). These diseases are commonly known as Synucleinopathies. Approximately 250,000 people are affected with synucleinopathies in the UK, and currently, no cure exists to stop or slow the disease progression. In all synucleinopathies, α-synuclein protein, at certain conditions, begin to stick to each other and form ‘aggregates’, which are known to damage and destroy neurons and other cells in the CNS. However, we do not entirely understand how these aggregates form, how they spread through the CNS and which type of aggregates is the most damaging. We also do not know why the different synucleinopathies show varying clinical symptoms, variable rates of disease progression and different ages of disease onset. Our mechanistic understanding of these diseases is limited, at least in part, by the lack of sensitive methods and relevant modelling systems. To understand this problem, I will use human-derived cell models which are reprogrammed from the skin cells of PD, DLB and MSA patients. These models will recapitulate the aggregation and spread of α-synuclein, as it happens in the diseased CNS. Using an ultrasensitive imaging methodology, I will identify, track and quantify the structure and function of individual α-synuclein aggregates which will form during the aggregation process and thus, I will determine the underlying mechanism of synucleinopathies.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL