Unravelling the complexity of α-Syn fibril polymorphism

Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and related disorders, are becoming the major public health issues in the elderly population. The increased rate of these incurable neurodegenerative disorders has devastating impacts on individuals and their families. 

Neurodegeneration starts from an abnormal accumulation of a protein in the brain, which interferes with its normal functions and impairs the patient’s ability to carry out daily activities. The condition worsens over time until it becomes full-blown dementia. More concerning is that these neurodegenerative disorders are variable and show differences in clinical and pathological representations. In prion diseases, such as Creutzfeldt–Jakob disease (CJD) and Kuru diseases, this variability has been linked to the presence of ‘strains’ of protein aggregates in the brain. These protein strains emerge due to structural variations in protein aggregates and induce differences in disease symptoms, incubation period, the severity of the disease, and pathology, similar to bacterial or viral strains. The proteins like α-synuclein (α-Syn), amyloid-β (Aβ), and tau are believed to exhibit prion-like strain behaviour and display polymorphism in their aggregates. As a result of amyloid polymorphism, it becomes challenging to identify the potential targets for developing drugs to reduce the progression of these diseases. 

Our research primarily addresses how a single protein (like α-Syn) can exist in different forms under identical aggregating conditions. Upon cellular or environmental insults, α-Syn undergoes structural conversion from a disordered state to amyloid form. During that conversion process, it forms heterogeneous and metastable aggregation intermediates, which are usually difficult to track. We designed an in vitro model system where we could monitor and isolate these aggregation intermediates. We found that these aggregation intermediates can convert into structurally diverse and biologically active polymorphs of α-Syn protein. These polymorphs differentially internalise in neuronal and glial cells, seed their endogenous monomeric counterpart, and transfer from one cell to another, reminiscent of prions. Thus, our work offers a novel approach to studying complex aggregation pathways and provides insights into the origin of fibril polymorphism, which could be beneficial in the future for designing conformational-based drugs against PD and related disorders.