Salivary α-synuclein and DJ-1: potential biomarkers for Parkinson's disease

Devic, Ivana; Hwang, Hye‐Jin; Edgar, J. Scott; Izutsu, Kenneth T.; Presland, Richard B.; Pan, Catherine; Goodlett, David R.; Wang, Yu; Armaly, Jeff; Tumas, Vítor; Zabetian, Cyrus P.; Leverenz, James B.; Shi, Min; Zhang, Jing

doi:10.1093/brain/awr015

Cited by 207 publications

(208 citation statements)

References 22 publications

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“…a-Syn can leave cells via various mechanisms including secretion and, more specifically, exocytosis (Figure 2a). Multiple forms of a-syn have been detected in cerebrospinal fluid, blood plasma, [44][45][46] and more recently, in saliva, 47 indicating a secretory process. Monomers and aggregated forms of a-syn are secreted from neuroblastoma cells overexpressing a-syn and from rat primary cortical neurons.…”

Section: Molecular Mechanisms Involved In Intercellular Transfer Of Amentioning

confidence: 99%

A deadly spread: cellular mechanisms of α-synuclein transfer

2011

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Classically, Parkinson's disease (PD) is linked to dopamine neuron death in the substantia nigra pars compacta. Intracytoplasmic protein inclusions named Lewy bodies, and corresponding Lewy neurites found in neuronal processes, are also key features of the degenerative process in the substantia nigra. The molecular mechanisms by which substantia nigra dopamine neurons die and whether the Lewy pathology is directly involved in the cell death pathway are open questions. More recently, it has become apparent that Lewy pathology gradually involves greater parts of the PD brain and is widespread in late stages. In this review, we first discuss the role of misfolded a-synuclein protein, which is the main constituent of Lewy bodies, in the pathogenesis of PD. We then describe recent evidence that a-synuclein might transfer between cells in PD brains. We discuss in detail the possible molecular mechanisms underlying the proposed propagation and the likely consequences for cells that take up a-synuclein. Finally, we focus on aspects of the pathogenic process that could be targeted with new pharmaceutical therapies or used to develop biomarkers for early PD detection. Multiple hypotheses exist to help explain dopamine neuron cell death and Lewy body formation observed in Parkinson's disease (PD). Mutations of the main proteinaceous constituent of Lewy bodies, a-synuclein (a-syn), lead to dominant, familial disease forms. [1][2][3][4][5] More recently, genome-wide association studies (GWASs) identified variants of the a-synuclein gene (SNCA) gene, encoding a-syn protein, that are coupled to increased PD susceptibility, thus clearly linking this protein to idiopathic PD. 6-8 Furthermore, overexpressed and/or misfolded a-syn is pathogenic to cells while a-syn can be secreted from cells, enter other cells, and seed small intracellular aggregates, demonstrating a connection between a-syn and pathogenic mechanisms of PD. [9][10][11][12][13][14][15][16] In parallel, a much-discussed hypothesis by Braak and colleagues 17 states that a pathogenic agent, introduced via ingestion and/or inhalation, may transfer from the entry site along known long, unmyelinated axons to basal brain areas and eventually to brain stem and cortical regions. Although a-syn is unlikely to be this initial pathogen, it might be the initial target of the unknown agent. If a-syn is misfolded because of the action of the unknown agent, it might contribute to the spreading of pathology by moving from one cell to another and triggering misfolding in the recipient cells. If so, it might explain the surprising presence of Lewy bodies in the young neural grafts of transplanted PD patients observed more than a decade after surgery. [18][19][20][21] In this review, we discuss possible mechanisms by which a-syn could spread between cells and have deadly consequences by describing the molecular evidence for a-syn cellular exit, transit to other cells, uptake by cells, intracellular aggregation, and responses to a-syn accumulation.The Relationship Between a-Syn and PD ...

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Section: Molecular Mechanisms Involved In Intercellular Transfer Of Amentioning

confidence: 99%

A deadly spread: cellular mechanisms of α-synuclein transfer

2011

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“…The function of salivary glands may be affected in PD, manifesting as hyposalivation and abnormal saliva composition [2]. DJ--1 is a protein involved in diseases associated with aggregated alpha--synuclein and has previously been examined as a potential biomarker of PD in CSF, blood, and saliva [3]. In this cross--sectional study, we examined saliva from a group of patients with PD and age--matched controls in order to identify abnormalities in saliva gland function among patients, as well as to determine whether changes in the levels of specific proteins, such as DJ--1, may be useful biomarkers of disease.…”

Section: Introductionmentioning

confidence: 99%

Elevated salivary protein in Parkinson's disease and salivary DJ-1 as a potential marker of disease severity

Masters

Noyce

Warner³

et al. 2015

Parkinsonism & Related Disorders

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“…47) DJ-1 is localized in the cytoplasm, nucleus and mitochondria 26,48) and is secreted into culture medium [49][50][51] or serum, [52][53][54][55][56][57][58][59] cerebrospinal fluid, 53,54,60) saliva 61,62) and nipple fluid. 63) DJ-1 is translocated from the cytoplasm to nucleus upon addition of a mitogen to the culture medium 26) and is translocated to mitochondria after oxidative stress.…”

Section: Tumor Suppressor Mm-1 and Neurodegenerationmentioning

confidence: 99%

Common Mechanisms of Onset of Cancer and Neurodegenerative Diseases

Ariga

2015

Biological & Pharmaceutical Bulletin

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Onset of cancer and neurodegenerative disease occurs by abnormal cell growth and neuronal cell death, respectively, and the number of patients with both diseases has been increasing in parallel with an increase in mean lifetime, especially in developed countries. Although both diseases are sporadic, about 10% of the diseases are genetically inherited, and analyses of such familial forms of gene products have contributed to an understanding of the molecular mechanisms underlying the onset and pathogenesis of these diseases. I have been working on c-myc, a protooncogene, for a long time and identified various c-Myc-binding proteins that play roles in c-Myc-derived tumorigenesis. Among these proteins, some proteins have been found to be also responsible for the onset of neurodegenerative diseases, including Parkinson's disease, retinitis pigmentosa and cerebellar atrophy. In this review, I summarize our findings indicating the common mechanisms of onset between cancer and neurodegenerative diseases, with a focus on genes such as DJ-1 and Myc-Modulator 1 (MM-1) and signaling pathways that contribute to the onset and pathogenesis of cancer and neurodegenerative diseases.

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Salivary α-synuclein and DJ-1: potential biomarkers for Parkinson's disease

Cited by 207 publications

References 22 publications

A deadly spread: cellular mechanisms of α-synuclein transfer

A deadly spread: cellular mechanisms of α-synuclein transfer

Elevated salivary protein in Parkinson's disease and salivary DJ-1 as a potential marker of disease severity

Common Mechanisms of Onset of Cancer and Neurodegenerative Diseases

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