Potential application of heat shock proteins as therapeutic targets in Parkinson's disease

Parkinson's disease (PD) is a chronic neurodegenerative disease and the second most common neurodegenerative disease after Alzheimer's disease (AD), and the mortality rate of this disease will increase significantly with the increase of population. Its main features include resting tremor, stiffness, bradykinesia, and postural instability (Jagadeesan et al., 2017), as well as secondary motor symptoms such as dystonia, and other clinical features such as autonomic dysfunction (Jankovic, 2008). Neuropathological features of PD include loss of dopaminergic neurons and α-Synuclein (α-Syn) rich protein aggregates (Zhang et al., 2018), which are hallmarks of its pathology and canonical biomarkers (Badanjak et al., 2021; Li and Le, 2020).

Oligomers formed during α-Syn aggregation are the most potent neurotoxic substances in PD pathogenesis (Winner et al., 2011), and α-Syn fibers play an important role in the spread and progression of the disease (Volpicelli-Daley et al., 2014). PD is associated with misfolding and aggregation of α-Syn, and autophagy is a major pathway for eliminating these proteins to prevent them from damaging cells, thereby maintaining neuronal survival. In PD, autophagy is defective, resulting in an imbalance of neuronal homeostasis and increased numbers of autophagosomes in patient brain tissue, and the autophagy defects are also present in many animal models of PD, such as MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), 6-OHDA (6-hydroxydopamine), or rotenone-induced (Liu et al., 2019). Normally, there is a balance between apoptosis and autophagy to maintain cellular homeostasis. However, various studies have reported that the autophagy-lysosomal system is impaired in postmortem tissues of PD patients and in PD models, leading to apoptosis significantly increased (Liu et al., 2018a). Therefore, inhibiting the misfolding and aggregation of α-Syn, regulating apoptosis and autophagy are effective means to treat PD.

The heat shock proteins (HSPs) are a class of heat stress proteins that widely exist from bacteria to mammals with molecular chaperone activity. HSPs can correctly fold newly synthesized peptides and transport and degrade mature proteins, and play an important role in maintaining cellular protein homeostasis (Ellis, 1990; Morimoto et al., 1992). In vitro, α-Syn aggregation can be inhibited by HSPs, such as HSP70, small HSPs, and HSP40 (Kampinga and Bergink, 2016). Overexpression of these HSPs has been shown to reduce α-Syn aggregation in multiple PD cell models and mouse models (Klucken et al., 2004). HSPs can mediate the autophagy pathway and help proteins localize to autophagosomes for targeted elimination of α-Syn aggregates. In addition, HSPs can also inhibit apoptosis by regulating various signaling pathways. And there are many compounds that can promote or inhibit HSPs, such as geldanamycin and melatonin. Therefore, HSPs can be potential targets for PD protection strategies. This review focuses on the physiological functions and action mechanisms of different HSPs on PD, as well as the advanced progress and prospects of targeting HSPs in the treatment of PD.

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