Cell-autonomous and non-cell-autonomous drivers of dopamine neuron vulnerability in Parkinson’s disease

The motor symptoms of Parkinson’s disease are linked to age-dependent degeneration of dopamine neurons. Traditionally, the loss of these neurons has been thought to stem mainly from cell-autonomous cellular dysfunctions. However, there is growing evidence suggesting it could result from complex interactions between cell-autonomous and non-cell-autonomous mechanisms. This review examines evidence for cell-autonomous mechanisms linked to mitochondrial, lysosomal or proteasomal perturbations, and for non-cell-autonomous processes arising from glial and peripheral immune cells. We discuss how these pathways can converge to create chronic cellular stress and trigger cell death mechanisms. Beyond highlighting apoptosis as a key mode of degeneration, we consider the contribution of other mechanisms including pyroptosis and ferroptosis. Understanding the relative dominance of these mechanisms across disease stages and patient subgroups could help guide the development of mechanism-based neuroprotective strategies.