Newcastle University

Lewy bodies are intracellular inclusions of the protein α-synuclein and are the characteristic neuropathological lesion associated with dementia with Lewy bodies and Parkinson's disease, collectively termed Lewy body diseases. α-synuclein is an intrinsically disordered synaptic protein normally present throughout the brain but, for unknown reasons, aggregates into larger structures characterised by β-pleated sheet conformations in Lewy body diseases. Aggregated α-synuclein is thought to impair cellular function, either through loss of the normal function of α-synuclein or by gain of a neurotoxic function.

Increasing evidence suggests that Lewy body pathology may spread through the brain in a manner reminiscent of that previously described for prion protein, with α-synuclein spreading through the brain on the basis of anatomical connectivity. The mechanism underlying ‘prion-like’ spread suggests that aggregated α-synuclein, when introduced into native α-synuclein, acts as a template to induce its misfolding, thus propagating pathology throughout the brain. However, some regions of the brain with strong anatomical connectivity to early predilection sites do not typically manifest Lewy body pathology, suggesting that region- or cell- autonomous factors may mediate the vulnerability of Lewy body pathology to propagate.

The aim of this project is to utilise post-mortem human brain tissue and cultured neuronal cells to evaluate the transcriptomic and proteomic profile of vulnerable neurons compared to those with greater resilience to Lewy body pathology. The overall goal of this approach is to identify mediators of cellular vulnerability and resilience, and highlight pathways which may be amenable to therapeutic intervention.

 This project is led by Dr Daniel Erskine and is funded by Alzheimer’s Research UK.

 

Publication

Erskine D, Patterson L, Alexandris A, Hanson PS, McKeith IG, Attems J, Morris CM (2017). Regional levels of physiological alpha-synuclein are directly associated with Lewy body pathology. Acta Neuropathologica, in press.