Parkinson's disease (PD) is characterized by the progressive degeneration of 
substantia nigra pars compacta (SNpc) dopaminergic neurones and the formation of 
Lewy bodies (LB) in a proportion of the remaining neurones. α-synuclein is the 
main component of LB, but the pathological mechanisms that lead to 
neurodegeneration associated with LB formation remain unclear. Three pivotal 
elements have emerged in the development of PD: α-synuclein, mitochondria and 
protein degradation systems. We previously reported a unique model, created by 
conditional genetic depletion of 26S proteasomes in the SNpc of mice, which 
mechanistically links these three elements with the neuropathology of PD: 
progressive neurodegeneration and intraneuronal inclusion formation. Using this 
model, we tested the hypothesis that α-synuclein was essential for the formation 
of inclusions and neurodegeneration caused by 26S proteasomal depletion. We 
found that both of these processes were independent of α-synuclein. This 
provides an important insight into the relationship between the proteasome, 
α-synuclein, inclusion formation and neurodegeneration. We also show that the 
autophagy-lysosomal pathway is not activated in 26S proteasome-depleted 
neurones. This leads us to suggest that the paranuclear accumulation of 
mitochondria in inclusions in our model may reflect a role for the ubiquitin 
proteasome system in mitochondrial homeostasis and that neurodegeneration may be 
mediated through mitochondrial factors linked to inclusion biogenesis.