Fig. 3: The interplay between proteasome impairment and α-synuclein accumulation in PD.
From: Expanding the role of proteasome homeostasis in Parkinson’s disease: beyond protein breakdown
Under physiological state, α-synuclein is highly soluble and enriched at presynaptic terminals, which can be degraded through ubiquitin-dependent and ubiquitin-independent manner, so as to maintain the survival of neurons. In PD, α-synuclein accumulates in neuronal cell bodies to form a major component of aberrant aggregates known as Lewy bodies. α-synuclein is able to transform in different conformations, including monomers, oligomers (soluble conformations), and fibrils (insoluble conformations). The impairment of proteasome function resulting from the decreased subunits expression and proteolytic activities disturbs the degradation of substrates. Additionally, α-synuclein has been reported to inhibit the function of proteasome, which further aggravates the accumulation of α-synuclein. This suggests a vicious cycle between proteasomal impairment and proteotoxicity in PD.
