The use of the proteasome inhibitor lactacystin for modeling Parkinson’s disease: Early neurophysiological biomarkers and candidates for intranigral and extranigral neuroprotection

Екимова, И. В.; Белан, Дарья Владимировна; Lapshina, K. V.; Pastukhov, Yu. F.

doi:10.1016/b978-0-323-89833-1.00008-2

Cited by 3 publications

(4 citation statements)

References 58 publications

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“…Neuroprotective interventions are most effective at the early (preclinical) stage of the pathological process. Therefore, we utilized a previously developed LC-induced model [21,55] that reproduces the main pathogenetic signs of the preclinical stage of PD in rats. These include the degeneration of 27% of DA neurons in the SNpc (a level that is characteristic of the preclinical PD stage [8] (Figure S1), development of α-syn pathology (Figure 3), and signs of chronic neuroinflammation (Figures 5 and 6)).…”

Section: Discussionmentioning

confidence: 99%

“…To assess the therapeutic potential of exogenous GRP78, we used an LC-induced model of PD in rats, reproducing key pathological signs of PD [20,21]. At a dose of 0.4 µg, LC was injected into each side of the SNpc twice, with a 7-day interval (n = 8, group LC).…”

Section: Grp78 Treatment Prevents Neuronal Loss In the Substantia Nig...mentioning

confidence: 99%

“…The weakening of conformational control mechanisms ensured by heat shock proteins also contributes to protein aggregation [17][18][19]. The discovery of UPS functional insufficiency in familial and sporadic PD has promoted the development of novel in vivo PD models based on proteasome inhibitors, such as lactacystin (LC) [20,21]. LC is a metabolite of ubiquitous soil and water bacteria, e.g., Streptomyces lactacystinaeus.…”

Section: Introductionmentioning

confidence: 99%

“…Given the lipophilic properties of LC and its ability to enter the human body with food, water, or dust and accumulate over time, exposure to this proteasome inhibitor can underlie some cases of PD [22]. When injected directly into the SNpc in rats, LC replicates the key neuropathological features of PD in the nigrostriatal and extranigral systems stage by stage, with the effects varying in a dose-dependent manner [21]. This sets LC apart from other neurotoxins used to model PD, making it one of the most promising substances for testing therapeutic strategies that can slow down neurodegeneration at various stages of PD development.…”

Section: Introductionmentioning

confidence: 99%

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Intranasal Administration of GRP78 Protein (HSPA5) Confers Neuroprotection in a Lactacystin-Induced Rat Model of Parkinson’s Disease

Pazi,

Belan,

Komarova

et al. 2024

IJMS

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Grp78 Treatment Prevents Neuronal Loss In the Substantia Nig...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Intranasal Administration of GRP78 Protein (HSPA5) Confers Neuroprotection in a Lactacystin-Induced Rat Model of Parkinson’s Disease

Pazi,

Belan,

Komarova

et al. 2024

IJMS

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Pharmacological Inhibition of AQP4 Water Channel Activity Aggravates Alpha-Synuclein Pathology in the Substantia Nigra in a Rat Model of Parkinson’s Disease

Lapshina,

Khanina,

Kaismanova

et al. 2023

J Evol Biochem Phys

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Pharmacological Inhibition of the AQP4 Water Channel Activity Causes an Aggravation of Alpha-Synuclein Pathology in the Substantia Nigra in a Rat Model of Parkinson’s Disease

Lapshina,

Khanina,

Kaismanova

et al. 2023

Rossijskij fiziologičeskij žurnal im. I.M. Sečenova

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The misfolding of the protein α-synuclein, which leads to the formation of neurototoxic oligomers and aggregates, is one of the main causes of loss of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNpc) in Parkinson’s disease (PD). We previously found that pharmacological inhibition of the water channel aquaporin-4 (AQP4), participating in the mechanisms of brain clearance of amyloidogenic proteins, caused the aggravation of neurodegeneration in the nigrostriatal system and the development of motor disturbances in a lactacystin model of PD. It was hypothesized that the progression of neurodegeneration can be a result of the excessive accumulation of pathologic forms of α-synuclein due to the AQP4 inhibition. The aim of this study is to determine whether pharmacological inhibition of AQP4 activity in a rat model of preclinical PD leads to an aggravation in α-synuclein pathology. The experiments were performed on male Wistar rats. AQP4 activity was suppressed using the intracerebroventricular injection of inhibitor TGN-020. To reproduce the model of the preclinical stage of PD, a specific proteasome inhibitor lactacystin (LC) was used. It was injected bilaterally into the SNpc. Immunoblotting methods and confocal microscopy were applied. The LC model of PD was characterized by a pathologic accumulation of total water-soluble and Ser129-phosphorylated forms of α-synuclein, as well as by formation of insoluble α-synuclein aggregates in the DA-neurons of SNpc. TGN-020 caused a significant aggravation of α-synuclein pathology in the LC model of PD. It was manifested by a marked increase in the level of water-soluble and modified forms of α-synuclein and by the 1.9-fold rise in the amount of α-synuclein aggregates in SN. We suppose that the disfunction of AQP4 which is involved in glymphatic system functioning, can be one of the mechanisms leading to the neurodegeneration and accumulation of amyloidogenic proteins in brain parenchyma during PD. The water channel AQP4 might be a target for the development of new therapeutic approaches aimed at attenuation of the cytotoxicity, accumulation and distribution of α-synuclein during the development of PD-like pathology.

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The use of the proteasome inhibitor lactacystin for modeling Parkinson’s disease: Early neurophysiological biomarkers and candidates for intranigral and extranigral neuroprotection

Cited by 3 publications

References 58 publications

Intranasal Administration of GRP78 Protein (HSPA5) Confers Neuroprotection in a Lactacystin-Induced Rat Model of Parkinson’s Disease

Intranasal Administration of GRP78 Protein (HSPA5) Confers Neuroprotection in a Lactacystin-Induced Rat Model of Parkinson’s Disease

Pharmacological Inhibition of AQP4 Water Channel Activity Aggravates Alpha-Synuclein Pathology in the Substantia Nigra in a Rat Model of Parkinson’s Disease

Pharmacological Inhibition of the AQP4 Water Channel Activity Causes an Aggravation of Alpha-Synuclein Pathology in the Substantia Nigra in a Rat Model of Parkinson’s Disease

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