Down-regulation of Mortalin Exacerbates Aβ-mediated Mitochondrial Fragmentation and Dysfunction

Park, Soo‐Young; Shin, Ji Hyun; Jeong, Jae In; Song, Ji Hoon; Jo, Yoon Kyung; Kim, Eun Sung; Lee, Eunjoo H.; Hwang, Jung Jin; Lee, Eun Kyung; Chung, Sun Ju; Koh, Jae‐Young; Jo, Dong-Gyu; Cho, Dong‐Hyung

doi:10.1074/jbc.m113.492587

Cited by 59 publications

(55 citation statements)

References 71 publications

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“…In the brains of patients with AD, phosphorylation and S-nitrosylation of dynamin-related protein 1 (DRP1), which is a critical factor for mitochondrial fission, is increased, likely impacting mitochondrial structure [96,98]. In addition, mortalin seems to function in Ab-mediated mitochondrial fragmentation and dysfunction through DRP1 [99]. On the other hand, a recent report showed an opposite result that elongated mitochondria may contribute to neurodegeneration [100]; mislocalization of DRP1 triggered by tau-mediated F-actin stabilization leads to elongated mitochondria to promote neurodegeneration.…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

Amyloid beta receptors responsible for neurotoxicity and cellular defects in Alzheimer’s disease

Kam

Gwon

Jung

2014

Cell. Mol. Life Sci.

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Alzheimer's disease (AD) is the most common neurodegenerative disease. Although a major cause of AD is the accumulation of amyloid-β (Aβ) peptide that induces neuronal loss and cognitive impairments, our understanding of its neurotoxic mechanisms is limited. Recent studies have identified putative Aβ-binding receptors that mediate Aβ neurotoxicity in cells and models of AD. Once Aβ interacts with a receptor, a toxic signal is transduced into neurons, resulting in cellular defects including endoplasmic reticulum stress and mitochondrial dysfunction. In addition, Aβ can also be internalized into neurons through unidentified Aβ receptors and induces malfunction of subcellular organelles, which explains some part of Aβ neurotoxicity. Understanding the neurotoxic signaling initiated by Aβ-receptor binding and cellular defects provide insight into new therapeutic windows for AD. In the present review, we summarize the findings on Aβ-binding receptors and the neurotoxicity of oligomeric Aβ.

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Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

Amyloid beta receptors responsible for neurotoxicity and cellular defects in Alzheimer’s disease

Kam

Gwon

Jung

2014

Cell. Mol. Life Sci.

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“…Knocking in extra copies of a Caenorhabditis elegans homologue of mot-2 caused increase in their lifespan (19). These effects have been ascribed, in part, to the ability of mot-2 to (i) inactivate wild-type p53 functions including transcriptional activation (20,21), control of centrosome duplication (22), and deregulation of apoptosis in cancer cells (23)(24)(25); (ii) activate telomerase and hnRNP-K (26); (iii) and regulate oxidative stress (27,28) and mitochondrial structure (29,30). On the other hand, deficiency in mortalin has been well connected to the age-related pathologies including Alzheimer and Parkinson diseases (28,(31)(32)(33).…”

Section: Waf1mentioning

confidence: 99%

Functional Significance of Point Mutations in Stress Chaperone Mortalin and Their Relevance to Parkinson Disease

Wadhwa

Ryu

Ahn

et al. 2015

Journal of Biological Chemistry

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Background: Mortalin, an essential chaperone, is enriched in cancers; it possesses pro-proliferative and anti-apoptotic functions and has been found mutated in some Parkinson patients. Results: Mutant mortalins lack functions involved in carcinogenesis and cause increased oxidative stress; we demonstrate the factors and mechanism of their role in Parkinson disease. Conclusion: Mutations in mortalin contribute to Parkinson disease.Significance: This work contributes toward an understanding of mortalin-associated diseases for therapy.

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“…On the other hand, a role for mortalin in healthy astrocytes or its dysfunction in the astrocytes of neurodegenerative patients has not yet been described. Given that mortalin is known to be decreased in the brain tissue of not only PD patients, but also AD patients (16), the demonstration of the presence of mortalin within astrocytes is significant in that it opens the possibility that the protein is modulated in neurodegenerative disease in cell types other than neurons.…”

Section: Discussionmentioning

confidence: 99%

Mortalin is Expressed by Astrocytes and Decreased in the Midbrain of Parkinson's Disease Patients

et al. 2015

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Mortalin, an essential mitochondrial chaperone protein, has previously been implicated in the pathogenesis of a wide array of diseases, including neurodegenerative conditions such as Parkinson’s disease (PD) and Alzheimer’s disease. Previous reports have consistently described mortalin protein levels to be lower in the brain tissue of patients with neurodegenerative disease, with expression demonstrated to be lower in neurons of post-mortem PD brain specimens. However, to date, mortalin expression has not yet been evaluated in astrocytes of post-mortem brain tissue from either normal or PD subjects. Mortalin expression was demonstrated in mouse primary astrocyte cultures by Western blot and quantitative PCR. Furthermore, confocal microscopy studies in human post-mortem tissue indicated co-localization of mortalin within astrocytes. Utilizing a quantitative immunofluorescence staining approach, the protein was found to be moderately reduced (~35%) in this cell type in the substantia nigra pars compacta, but not structures of the corpus striatum, in PD subjects as compared to age/gender-matched controls. These findings highlight the potential contribution of disrupted astroglial function in the pathogenesis of PD.

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Down-regulation of Mortalin Exacerbates Aβ-mediated Mitochondrial Fragmentation and Dysfunction

Cited by 59 publications

References 71 publications

Amyloid beta receptors responsible for neurotoxicity and cellular defects in Alzheimer’s disease

Amyloid beta receptors responsible for neurotoxicity and cellular defects in Alzheimer’s disease

Functional Significance of Point Mutations in Stress Chaperone Mortalin and Their Relevance to Parkinson Disease

Mortalin is Expressed by Astrocytes and Decreased in the Midbrain of Parkinson's Disease Patients

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