Internalization, axonal transport and release of fibrillar forms of alpha-synuclein

Intra-neuronal protein aggregates made of fibrillar alpha-synuclein (α-syn) are the hallmark of Parkinson's disease (PD). With time, these aggregates spread through the brain following axonal projections. Understanding the mechanism of this spread is central to the study of the progressive nature of PD. Here we review data relevant to the uptake, transport and release of α-syn fibrils. We summarize several cell surface receptors that regulate the uptake of α-syn fibrils by neurons. The aggregates are then transported along axons, both in the anterograde and retrograde direction. The kinetics of transport suggests that they are part of the slow component b of axonal transport. Recent findings indicate that aggregated α-syn is secreted by neurons by non-canonical pathways that may implicate various molecular chaperones including USP19 and the DnaJ/Hsc70 complex. Additionally, α-syn fibrils may also be released and transmitted from neuron-to-neuron via exosomes and tunneling nanotubes. Understanding these different mechanisms and molecular players underlying α-syn spread is crucial for the development of therapies that could halt the progression of α-syn-related degenerative diseases.