Abstract
BackgroundAbnormal expression of major histocompatibility complex class I (MHC-I) is increased in dopaminergic (DA) neurons in the substantia nigra (SN) in Parkinson’s disease (PD). Low-molecular-mass protein 7 (β5i) is a proteolytic subunit of the immunoproteasome that regulates protein degradation and the MHC pathway in immune cells.MethodsIn this study, we investigated the role of β5i in DA neurons using a 6-hydroxydopamine (6-OHDA) model in vitro and vivo.ResultsWe showed that 6-OHDA upregulated β5i expression in DA neurons in a concentration- and time-dependent manner. Inhibition and downregulation of β5i induced the expression of glucose-regulated protein (Bip) and exacerbated 6-OHDA neurotoxicity in DA neurons. The inhibition of β5i further promoted the activation of Caspase 3-related pathways induced by 6-OHDA. β5i also activated transporter associated with antigen processing 1 (TAP1) and promoted MHC-I expression on DA neurons.ConclusionTaken together, our data suggest that β5i is activated in DA neurons under 6-OHDA treatment and may play a neuroprotective role in PD.
Highlights
Abnormal expression of major histocompatibility complex class I (MHC-I) is increased in dopaminergic (DA) neurons in the substantia nigra (SN) in Parkinson’s disease (PD)
We further explored the role of β5i in the loss of dopaminergic (DA) neurons under 6-hydroxydopamine (6-OHDA) insult in vitro and vivo
Immunoproteasome and MHC molecules are minimally expressed in the healthy brain, and their activation and upregulation are indicative of a pathological status in the central nervous system (CNS) [12, 19, 31, 32]
Summary
Abnormal expression of major histocompatibility complex class I (MHC-I) is increased in dopaminergic (DA) neurons in the substantia nigra (SN) in Parkinson’s disease (PD). Accumulation of aggregated and misfolded protein aggregates, and neuroinflammation have been suggested to play roles in the pathogenesis of Parkinson’s disease (PD) [1, 2] These factors impair the ubiquitin-proteasome system (UPS) which is critical for protein metabolic homeostasis [3,4,5], and they promote the replacement of constitutive proteasome subunits β1, β2 and β5 by the respective immunoproteasome catalytic subunits β1i/ low-molecular-mass protein 2 (LMP2, PSMB9), β2i/multicatalytic endo- peptidase complex-like 1 (MECL1, PSMB10) and β5i (LMP7, PSMB8) [6,7,8]. The immunoproteasome helps to degrade abnormal proteins, present cleaved peptides as antigens to major histocompatibility complex (MHC) molecules and regulate neuroinflammation [9, 10]. In Huntington’s disease (HD), immunoproteasomes may contribute to the metabolism of huntingtin protein, which is not degraded by classical proteasomes [14].
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