Affiliation:
1. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 44 Thorez pr., St. Petersburg 194223, Russia
2. Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky pr., St. Petersburg 194064, Russia
Abstract
The accumulation of misfolded and aggregated α-synuclein can trigger endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), leading to apoptotic cell death in patients with Parkinson’s disease (PD). As the major ER chaperone, glucose-regulated protein 78 (GRP78/BiP/HSPA5) plays a key role in UPR regulation. GRP78 overexpression can modulate the UPR, block apoptosis, and promote the survival of nigral dopamine neurons in a rat model of α-synuclein pathology. Here, we explore the therapeutic potential of intranasal exogenous GRP78 for preventing or slowing PD-like neurodegeneration in a lactacystin-induced rat model. We show that intranasally-administered GRP78 rapidly enters the substantia nigra pars compacta (SNpc) and other afflicted brain regions. It is then internalized by neurons and microglia, preventing the development of the neurodegenerative process in the nigrostriatal system. Lactacystin-induced disturbances, such as the abnormal accumulation of phosphorylated pS129-α-synuclein and activation of the pro-apoptotic GRP78/PERK/eIF2α/CHOP/caspase-3,9 signaling pathway of the UPR, are substantially reversed upon GRP78 administration. Moreover, exogenous GRP78 inhibits both microglia activation and the production of proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), via the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway in model animals. The neuroprotective and anti-inflammatory potential of exogenous GRP78 may inform the development of effective therapeutic agents for PD and other synucleinopathies.
Reference74 articles.
1. Epidemiology of Parkinson’s Disease;Tysnes;J. Neural Transm.,2017
2. Projected Number of People with Parkinson Disease in the Most Populous Nations, 2005 through 2030;Dorsey;Neurology,2007
3. Parkinson’s Disease;Thomas;Hum. Mol. Genet.,2007
4. Is the Cause of Parkinson’s Disease Environmental or Hereditary? Evidence from Twin Studies;Tanner;Adv. Neurol.,2003
5. An Infection Hypothesis of Parkinson’s Disease;Karpenko;Neurosci. Behav. Physiol.,2019
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献