The causative nature of alpha-synuclein (α-syn) accumulation in Parkinson’s disease pathophysiology has been a subject of debate among researchers, ever since its identification in Lewy bodies. While some researchers believe that α-syn accumulation directly leads to the neurodegeneration observed in Parkinson’s disease, others argue that its build up may be a consequence of underlying cellular dysfunction or a protective response against cellular stress, rather than the primary cause of the disease.

The lack of a direct cause-effect relationship between α-syn aggregation and neurodegeneration in Parkinson’s disease, as well as the presence of Lewy bodies in other conditions, the occurrence of rare genetic forms of the disease that do not involve α-syn abnormalities, and the limited efficacy of α-syn targeting therapies thus far have cast doubt on the idea that α-syn is the sole causative factor in PD. While we cannot yet draw conclusions on its causative role, it is well accepted that α-syn plays a major role of PD and is therefore an important marker and potential target in the disease.

In this episode, experts discuss our current understanding of the role of α-syn in PD, as well as the possibility that the loss of normal α-syn function may be more relevant than the accumulation of insoluble α-syn in PD. We will hear from researchers working to improve the diagnosis and monitoring of PD, with the exciting development of novel α-syn-PET tracers and seed amplification assays that can detect early Parkinson’s disease with high sensitivity and specificity.

With Tiago Outeiro, PhD; Alberto Espay, MD, MSc; Francesca Capotosti, PhD; and Andrea Pilotto, MD.