MPTP-induced model of Parkinson's disease in heat shock protein 70.1 knockout mice

Park, Hyun Kyung; Cho, Ah Rang; Lee, Seung−Chul; Ban, Ju Yeon

doi:10.3892/mmr.2012.839

Cited by 5 publications

(1 citation statement)

References 26 publications

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“… 62–65 Similarly, genes encoding enzymes, such as increased p90Rsk and Dusp5, as well as decreased Prkcg and Map4k1, have been associated with neuroprotection. 66–69 We also observed the enhanced expression of genes encoding pro-survival heat shock proteins ( Hspa1a , Hspa1b and Hspa2 ), genotoxic stress proteins ( Gadd45a and Gadd45g ) and transcription factors ( Nr4a1 , Jun , Fos and Srf ) 70–77 ( Supplementary Figure S1M ).…”

Section: Discussionmentioning

confidence: 76%

Igf1 and Pacap rescue cerebellar granule neurons from apoptosis via a common transcriptional program

Maino

D’Agata

Severini

et al. 2015

Cell Death Discovery

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A shift of the delicate balance between apoptosis and survival-inducing signals determines the fate of neurons during the development of the central nervous system and its homeostasis throughout adulthood. Both pathways, promoting or protecting from apoptosis, trigger a transcriptional program. We conducted whole-genome expression profiling to decipher the transcriptional regulatory elements controlling the apoptotic/survival switch in cerebellar granule neurons following the induction of apoptosis by serum and potassium deprivation or their rescue by either insulin-like growth factor-1 (Igf1) or pituitary adenylyl cyclase-activating polypeptide (Pacap). Although depending on different upstream signaling pathways, the survival effects of Igf1 and Pacap converged into common transcriptional cascades, thus suggesting the existence of a general transcriptional program underlying neuronal survival.

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Section: Discussionmentioning

confidence: 76%

Igf1 and Pacap rescue cerebellar granule neurons from apoptosis via a common transcriptional program

Maino

D’Agata

Severini

et al. 2015

Cell Death Discovery

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PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model

Chiu

Weng

et al. 2018

Mol Neurobiol

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PARK14 patients with homozygous (D331Y) PLA2G6 mutation display motor deficits of pure early-onset Parkinson's disease (PD). The aim of this study is to investigate the pathogenic mechanism of mutant (D331Y) PLA2G6-induced PD. We generated knockin (KI) mouse model of PARK14 harboring homozygous (D331Y) PLA2G6 mutation. Then, we investigated neuropathological and neurological phenotypes of PLA2G6 KI mice and molecular pathogenic mechanisms of (D331Y) PLA2G6-induced degeneration of substantia nigra (SN) dopaminergic neurons. Six-or nine-month-old PLA2G6Y KI mice displayed early-onset cell death of SNpc dopaminergic neurons. Lewy body pathology was found in the SN of PLA2G6 mice. Six-or nine-month-old PLA2G6 KI mice exhibited early-onset parkinsonism phenotypes. Disrupted cristae of mitochondria were found in SNpc dopaminergic neurons of PLA2G6 mice. PLA2G6 mice displayed mitochondrial dysfunction and upregulated ROS production, which may lead to activation of apoptotic cascade. Upregulated protein levels of Grp78, IRE1, PERK, and CHOP, which are involved in activation of ER stress, were found in the SN of PLA2G6 mice. Protein expression of mitophagic proteins, including parkin and BNIP3, was downregulated in the SN of PLA2G6 mice, suggesting that (D331Y) PLA2G6 mutation causes mitophagy dysfunction. In the SN of PLA2G6 mice, mRNA levels of eight genes that are involved in neuroprotection/neurogenesis were decreased, while mRNA levels of two genes that promote apoptotic death were increased. Our results suggest that PARK14 (D331Y) PLA2G6 mutation causes degeneration of SNpc dopaminergic neurons by causing mitochondrial dysfunction, elevated ER stress, mitophagy impairment, and transcriptional abnormality.

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Malfunctioning of Chaperone-Mediated Autophagy in Parkinson’s Disease: Feats, Constraints, and Flaws of Modulators

et al. 2018

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Homeostatic regulation of class II programmed cell death/autophagy for the degradation and elimination of substandard organelles and defective proteins is decisive for the survival of dopaminergic neurons. Chaperone-mediated autophagy (CMA), one of the most highly dedicated self-sacrificing events, is accountable for the partial elimination of redundant soluble cytoplasmic proteins in Parkinson's disease (PD). CMA is characterized by the selective delivery of superfluous protein containing lysine-phenylalanine-glutamate-arginine-glutamine (KFERQ)/KFERQ-like motif to the lysosome through molecular chaperones, such as heat shock cognate-70 (Hsc-70). KFERQ/KFERQ-like motif present in the poor quality cytoplasmic substrate protein and Hsc-70 complex is recognized by a janitor protein, which is referred to as the lysosome-associated membrane protein-2A (LAMP-2A). This protein is known to facilitate an entry of substrate-chaperone complex in the lumen for hydrolytic cleavage of substrate and elimination of end-products. Impaired CMA is repeatedly blamed for an accumulation of surplus soluble proteins. However, it is still an enigma if CMA is a bonus or curse for PD. Case-control studies and cellular and animal models have deciphered the contribution of impaired CMA in PD. Current article updates the role of CMA in toxicant models and recapitulates the evidences that have highlighted a link between impaired CMA and PD. Although PD is an irreversible happening and CMA is a dual edging phenomenon, it is anticipated that fine-tuning of the latter encounters the former to a certain extent. Besides, the truth, embellishment, and propaganda regarding the issue are also emphasized in the final segment of the article.

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MPTP-induced model of Parkinson's disease in heat shock protein 70.1 knockout mice

Cited by 5 publications

References 26 publications

Igf1 and Pacap rescue cerebellar granule neurons from apoptosis via a common transcriptional program

Igf1 and Pacap rescue cerebellar granule neurons from apoptosis via a common transcriptional program

PARK14 (D331Y) PLA2G6 Causes Early-Onset Degeneration of Substantia Nigra Dopaminergic Neurons by Inducing Mitochondrial Dysfunction, ER Stress, Mitophagy Impairment and Transcriptional Dysregulation in a Knockin Mouse Model

Malfunctioning of Chaperone-Mediated Autophagy in Parkinson’s Disease: Feats, Constraints, and Flaws of Modulators

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