Mutational screening of the mortalin gene (HSPA9) in Parkinson’s disease

Mena, Lorena de; Coto, Eliécer; Sánchez-Ferrero, Elena; Ribacoba, René; Guisasola, Luis M.; Salvador, Carlos; Blázquez, Marta; Álvarez, Victoria

doi:10.1007/s00702-009-0273-2

Cited by 75 publications

(54 citation statements)

References 21 publications

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“…Consistent with this role, several studies have shown that mortalin may be implicated in the progression of neurodegenerative and protein aggregation disorders, such as Parkinson and Alzheimer (Burbulla et al 2010;De Mena et al 2009;Deocaris et al 2008;Deocaris et al 2007;Koren et al 2009;Shi et al 2008). Moreover, when mammalian mitochondria are challenged with an imported protein with a strong tendency to form aggregates, the mitochondrial unfolded protein response (mUPR) is activated (Aldridge et al 2007;Zhao et al 2002).…”

Section: Electronic Supplementary Materialsmentioning

confidence: 94%

Reactivation of protein aggregates by mortalin and Tid1—the human mitochondrial Hsp70 chaperone system

Iosefson

Sharon

Goloubinoff

et al. 2012

Cell Stress and Chaperones

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The mitochondrial 70-kDa heat shock protein (mtHsp70), also known in humans as mortalin, is a central component of the mitochondrial protein import motor and plays a key role in the folding of matrix-localized mitochondrial proteins. MtHsp70 is assisted by a member of the 40-kDa heat shock protein co-chaperone family named Tid1 and a nucleotide exchange factor. Whereas, yeast mtHsp70 has been extensively studied in the context of protein import in the mitochondria, and the bacterial 70-kDa heat shock protein was recently shown to act as an ATP-fuelled unfolding enzyme capable of detoxifying stably misfolded polypeptides into harmless natively refolded proteins, little is known about the molecular functions of the human mortalin in protein homeostasis. Here, we developed novel and efficient purification protocols for mortalin and the two spliced versions of Tid1, Tid1-S, and Tid1-L and showed that mortalin can mediate the in vitro ATP-dependent reactivation of stable-preformed heat-denatured model aggregates, with the assistance of Mge1 and either Tid1-L or Tid1-S co-chaperones or yeast Mdj1. Thus, in addition of being a central component of the protein import machinery, human mortalin together with Tid1, may serve as a protein disaggregating machine which, for lack of Hsp100/ClpB disaggregating co-chaperones, may carry alone the scavenging of toxic protein aggregates in stressed, diseased, or aging human mitochondria.

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Section: Electronic Supplementary Materialsmentioning

confidence: 94%

Reactivation of protein aggregates by mortalin and Tid1—the human mitochondrial Hsp70 chaperone system

Iosefson

Sharon

Goloubinoff

et al. 2012

Cell Stress and Chaperones

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“…Using an unbiased quantitative proteomic approach, Jin and colleagues have reported that mtHsp70 levels are decreased in the mitochondrial fraction of the substantia nigra in Parkinson's patients (Jin et al 2006). Furthermore, several variants of the gene that codes for mtHsp70 (HSPA9) have been found in a small cohort of late-onset Parkinson's patients (De Mena et al 2009). Some of the phenotypes associated with mtHsp70 mutations are characterized by mitochondrial dysfunction, such as Njemini et al 2007 respiratory incompetency and increased susceptibility to oxidative stress (Burbulla et al 2010;Goswami et al 2012).…”

Section: Heat Shock Proteins In Neurodegenerative Disorders and Agingmentioning

confidence: 99%

Heat shock proteins in neurodegenerative disorders and aging

Leak

2014

J. Cell Commun. Signal.

145

119

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Many members of the heat shock protein family act in unison to refold or degrade misfolded proteins. Some heat shock proteins also directly interfere with apoptosis. These homeostatic functions are especially important in proteinopathic neurodegenerative diseases, in which specific proteins misfold, aggregate, and kill cells through proteotoxic stress. Heat shock protein levels may be increased or decreased in these disorders, with the direction of the response depending on the individual heat shock protein, the disease, cell type, and brain region. Aging is also associated with an accrual of proteotoxic stress and modulates expression of several heat shock proteins. We speculate that the increase in some heat shock proteins in neurodegenerative conditions may be partly responsible for the slow progression of these disorders, whereas the increase in some heat shock proteins with aging may help delay senescence. The protective nature of many heat shock proteins in experimental models of neurodegeneration supports these hypotheses. Furthermore, some heat shock proteins appear to be expressed at higher levels in longer-lived species. However, increases in heat shock proteins may be insufficient to override overwhelming proteotoxic stress or reverse the course of these conditions, because the expression of several other heat shock proteins and endogenous defense systems is lowered. In this review we describe a number of stressinduced changes in heat shock proteins as a function of age and neurodegenerative pathology, with an emphasis on the heat shock protein 70 (Hsp70) family and the two most common proteinopathic disorders of the brain, Alzheimer's and Parkinson's disease.

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“…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). Genomic studies have identified mutants of mortalin in PD patients from Swedish and German populations (31,32). In light of this information and to resolve the functional significance of these mutants in aging and age pathologies, we generated human cells expressing mot-1 or mortalin-PD (mot-PD) mutant proteins.…”

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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Mutational screening of the mortalin gene (HSPA9) in Parkinson’s disease

Cited by 75 publications

References 21 publications

Reactivation of protein aggregates by mortalin and Tid1—the human mitochondrial Hsp70 chaperone system

Reactivation of protein aggregates by mortalin and Tid1—the human mitochondrial Hsp70 chaperone system

Heat shock proteins in neurodegenerative disorders and aging

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

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