Molecular targets for modulating the protein translation vital to proteostasis and neuron degeneration in Parkinson's disease

Abstract

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, which is characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta concomitant with Lewy body formation in affected brain areas. The detailed pathogenic mechanisms underlying the selective loss of dopaminergic neurons in PD are unclear, and no drugs or treatments have been developed to alleviate progressive dopaminergic neuron degeneration in PD. However, the formation of α-synuclein-positive protein aggregates in Lewy body has been identified as a common pathological feature of PD, possibly stemming from the consequence of protein misfolding and dysfunctional proteostasis. Proteostasis is the mechanism for maintaining protein homeostasis via modulation of protein translation, enhancement of chaperone capacity and the prompt clearance of misfolded protein by the ubiquitin proteasome system and autophagy. Deregulated protein translation and impaired capacities of chaperone or protein degradation can disturb proteostasis processes, leading to pathological protein aggregation and neurodegeneration in PD. In recent years, multiple molecular targets in the modulation of protein translation vital to proteostasis and dopaminergic neuron degeneration have been identified. The potential pathophysiological and therapeutic significance of these molecular targets to neurodegeneration in PD is highlighted.

Keywords: Molecular targets; Neuron degeneration; Parkinson’s disease; Protein aggregation; Protein translation; Proteostasis.

Fig. 1

Molecular mechanisms for proteostasis maintenance Proteostasis can be maintained via three distinct and interlinked mechanisms, including the modulation of protein biogenesis, enhancement of chaperone capacity and prompt clearance of misfolded protein by UPS and autophagy. The ribosomal synthesis of nascent polypeptide is exquisitely modulated. The synthesized polypeptide can be folded into functional proteins with the assistance of chaperones. Chaperones can also function to refold stress-induced misfolded proteins. The misfolded protein can be cleared away by UPS and autophagy. However, the deregulated modulation of protein biogenesis and impairment of chaperone function, UPS and autophagy capacities can lead to disturbed proteostasis and protein aggregate formation

Fig. 2

Balance and imbalance of proteostasis implicated in PD pathogenesis Under physiological conditions, the modulation of protein biogenesis, chaperone capacity and protein degradation can counteract against deleterious factors and stress challenge-induced protein misfolding and proteostasis dysfunction (a). Under pathological conditions, such as PD-associated gene mutations, environmental toxin challenges and pathological aging, the protective capacities of the proteostasis mechanisms are impaired, whereas stress-induced protein misfolding, mitochondria impairment and oxidative stress are aggravated. This can lead to the imbalance of proteostasis and protein aggregation, contributing to neurodegeneration in PD (b)

Fig. 3

Molecular targets in the modulation of protein translation initiation implicated in proteostasis and PD pathogenesis and therapy Ribosomal protein biogenesis can be exquisitely modulated on multiple targets mainly through the modulation of functions of protein targets via phosphorylation and dephosphorylation by kinases and phosphatases, respectively. Multiple factors including eIF4G1, eIF4E, eIF4A, eIF3, eIF5, and eIF2 take part in the formation of the translation initiation complex, which is vital for initiation of protein translation. The kinase-induced phosphorylation of eIF4E, 4E-BP1, RPS15 and RPS6 will facilitate protein translation, which is supposed to be adverse to the maintenance of proteostasis under stress and implicated in PD pathogenesis. Mnk1 can phosphorylate eIF4E to enhance its binding with eIF4G1 to promote translation initiation, which can be abrogated by eIF4G2 chelation. However, the function of eIF4E can be inhibited by 4E-BP1 sequestration, which can be abrogated by LRRK2 and mTORC1 kinase-induced 4E-BP1 phosphorylation. LRRK2 kinase can also phosphorylate RPS15 to enhance protein translation, whereas mTORC1 kinase can phosphorylate S6K1. The phosphorylated S6K1 subsequently phosphorylates RPS6, which in turn promotes protein translation. LRRK2 and mTORC1 kinase inhibitors are supposed to have potential therapeutic effects against neurodegeneration in PD. On the other hand, the phosphorylation of eIF2α by PERK kinases can inhibit protein biogenesis. However, GADD34 can direct PP1 to dephosphorylate eIF2α, which can restore protein translation. GBZ can block GADD34 to promote eIF2α phosphorylation and arrest protein translation, whereas GSK2606414 can inhibit kinase-induced eIF2α phosphorylation to recover protein biogenesis. ISRIB, Trazodone and DBM can function downstream of eIF2α phosphorylation without influence on eIF2α phosphorylation to promote protein translation. However, all three FDA-approved drugs (GBZ, Trazodone and DBM) claim to have protective capacities against neurodegeneration in PD