The roles of connectivity and neuronal phenotype in determining the pattern of α-synuclein pathology in Parkinson's disease

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and motor dysfunction has been attributed to loss of dopaminergic neurons. However, motor dysfunction is only one of many symptoms experienced by patients. A neuropathological hallmark of PD is intraneuronal protein aggregates called Lewy pathology (LP). Neuropathological staging studies have shown that dopaminergic neurons are only one of the many cell types prone to manifest LP. Progressive appearance of LP in multiple brain regions, as well as pe-ripheral nerves, has led to the popular hypothesis that LP and misfolded forms of one of its major components - alpha-synuclein (aSYN) - can spread through synaptically connected circuits. However, not all brain regions or neurons within connected circuits develop LP, suggesting that cell autonomous factors modulate the develop-ment of pathology. Here, we review studies about how LP develops and progressively engages additional brain regions. We focus on how connectivity constrains progression and discuss cell autonomous factors that drive pathology development. We propose a mixed model of cell autonomous factors and trans-synaptic spread as mediators of pathology progression and put forward this model as a framework for future experiments exploring PD pathophysiology.