Pale Body-Like Inclusion Formation and Neurodegeneration following Depletion of 26S Proteasomes in Mouse Brain Neurones are Independent of α-Synuclein

Abstract

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.

Regulation of proteasome activity in health and disease

“…As tau, α-synuclein monomers are unfolded [171] and can be degraded by the 20S core particle without prior ubiquitination and in the absence of the RP [172]. Other studies, however, showed that depletion of the proteasome subunit Rpt2 results in accumulation of α-synuclein and the development of Lewy Body-like inclusions in mice, suggesting a role for the RP in α-synuclein degradation [173, 174]. This hypothesis is supported by a recent study of German PD patients, which found that variations in the gene PSMC4/Rpt3 correlated with the age of PD onset [175].…”

Limelight on Alpha-Synuclein: Pathological and Mechanistic Implications in Neurodegeneration

“…Similarly, in conditional knock-out mice, 26S proteasomal depletion is sufficient to drive neurodegeneration and to induce formation of ubiquitinated Lewy-like inclusions that are positive for ASYN aggregation [204]. However, inclusion formation and neurodegeneration in mice, caused by genetic depletion of 26S proteasomes, both occur independently of ASYN [205].…”

Lysosomes, autophagosomes and Alzheimer pathology in dementia with Lewy body disease

“…14 There is good evidence that basic failures within proteolytic pathways, particularly those involving UPS, result in the accumulation of aggregated forms of α-synuclein, and therefore may underpin the pathogenesis of LBD. 17 Conversely, other studies point to a dysfunction of lysosomal pathways. 15 Mutations in the PARK2 gene encoding Parkin, an E3 ubiquitin ligase, cause an autosomal recessive form of early-onset PD 11 and missense mutations in the PARK5 gene, encoding ubiquitin C-terminal hydrolase-L1 (UCH-L1), cause a familial form of PD.…”

“…12 Reduced expression of proteasomal subunits has been reported within the SN of patients with PD 13,14 and DLB, 16 and knockdown of 26S proteasome function leads to neurodegeneration. 17 Conversely, other studies point to a dysfunction of lysosomal pathways. For example, Gaucher's disease is a rare lysosomal storage disease caused by homozygous mutations in the GBA1 gene encoding the lysosomal hydrolytic enzyme glucosylceramidase, leading to toxic accumulation of its substrate (glucosylceramide) within lysosomes.…”