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Distinct lysosomal network protein profiles in parkinsonian syndrome cerebrospinal fluid
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. CBD Solutions, Stockholm, Sweden.
Memory and Aging Center, University of California, San Francisco, United States.
Memory and Aging Center, University of California, San Francisco, United States.
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2016 (English)In: Journal of Parkinson's Disease, ISSN 1877-7171, E-ISSN 1877-718X, Vol. 6, no 2, 307-315 p.Article in journal (Refereed) Published
Abstract [en]

Introduction: Clinical diagnosis of parkinsonian syndromes like Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy is hampered by overlapping symptomatology and lack of biomarkers for diagnosis, and definitive diagnosis is only possible post-mortem. Since impaired protein degradation plays an important role in many neurodegenerative disorders, we hypothesized that levels and profiles of lysosomal network proteins in cerebrospinal fluid could be changed in these parkinsonian syndromes.

Methods: Cerebrospinal fluid samples were collected from Parkinson’s disease patients (n=18), clinically diagnosed 4-repeat tauopathy patients, corticobasal syndrome (n=6) and progressive supranuclear palsy (n=5), pathologically diagnosed progressive supranuclear palsy (n=8) and corticobasal degeneration patients (n=7). Each patient set was compared to its appropriate control group consisting of the same number of age and gender matched individuals. Lysosomal network protein levels were detected via Western blotting.

Results: Lysosomal network proteins have markedly different cerebrospinal fluid protein levels and profiles in Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy. Lysosomal-associated membrane proteins 1 and 2 were significantly decreased in Parkinson´s disease; early endosomal antigen 1 was decreased and lysozyme increased in progressive supranuclear palsy; and lysosomal-associated membrane proteins 1 and 2, microtubule-associated protein 1 light chain 3 and lysozyme were increased in corticobasal degeneration.

Conclusions: Lysosomal network proteins hold promise of being interesting novel candidates for biomarker studies and for elucidating disease mechanisms of Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy, but further validation studies will be needed to assess the specificity and the predictive value of these proteins in CSF.

Place, publisher, year, edition, pages
IOS Press, 2016. Vol. 6, no 2, 307-315 p.
National Category
Cell and Molecular Biology Chemical Sciences
Identifiers
URN: urn:nbn:se:liu:diva-122342DOI: 10.3233/JPD-150759ISI: 000378352200004OAI: oai:DiVA.org:liu-122342DiVA: diva2:865682
Note

Funding agencies:This work was supported by the Swedish Alzheimer foundation, the Swedish Dementia foundation, Linkoping University Neurobiology Center, Karin & Sten CBD Solutions AB, AZ-KI TSC, ALF, US National Institutes of Health R01AG038791 and U54NS092089, the Tau Consortium, the Hellman Family Foundation.

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Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2016-08-01Bibliographically approved
In thesis
1. Lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease
Open this publication in new window or tab >>Lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The pre-symptomatic stage of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) occurs several decades before the clinical onset. Changes in the lysosomal network, i.e. the autophagosomal, endosomal and lysosomal vesicular system, are among the first alterations observed. There are currently no treatments to slow or cure neurodegenerative diseases, and there is a great need for discovery of treatment targets in cellular pathways where pathology pre-dates the neuronal death. It is also crucial to be able to diagnose neurodegenerative diseases earlier, both to enable early intervention treatment and aid in selecting clinical trial populations before the patient has widespread pathology.

This thesis aims at investigating the potential of lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease.

A targeted search for lysosomal network proteins was performed in cerebrospinal fluid (CSF) from AD patients, and seven proteins: early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), lysozyme, microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were elevated. The levels of EEA1, LAMP-1, LAMP-2, LC3, lysozyme and Rab3 were also measured in CSF from parkinsonian syndrome patients: PD, clinically diagnosed 4-repeat tauopathy, pathologically confirmed corticobasal degeneration (CBD) and pathologically confirmed progressive supranuclear palsy (PSP) patients. LAMP-1 and LAMP-2 were decreased in PD. LC3 and lysozyme levels were increased in 4-repeat tauopathy patients. EEA1 was decreased and lysozyme increased in PSP, and LAMP-1, LAMP-2, LC3 and lysozyme were increased in CBD. The lysosomal network proteins had different CSF protein profiles in all the parkinsonian syndromes, as well as in AD. It should be emphasized that only a select few of the lysosomal network proteins were observed to be changed, rather than a general change in lysosomal network proteins, which implicates the involvement of these seven proteins in specific pathological processes. The most interesting candidates, LAMP-2 and lysozyme, were selected for further study for their involvement in the pathology of AD.

Lysozyme was found to co-localise with Aβ plaques in AD patients and overexpression prolonged survival and improved the activity in a Drosophila model of AD. Lysozyme was found to alter the aggregation pathway of Aβ1-42, to counteract the formation of toxic Aβ species and to protect from Aβ1-42 induced cell toxicity. Aβ1-42 in turn was found to increase the expression of lysozyme in both neuronal and glial cells. These data suggest that lysozyme levels rise in AD as a compensatory response which is protective against Aβ associated toxicity.

LAMP-2 mRNA and protein were found increased in brain areas relevant for AD pathology and various cellular models showed complex involvement of LAMP-2 in Aβ related pathology, with extensive crosstalk between LAMP-2 and Aβ. Exposure to oligomeric Aβ1-42 caused an upregulation of LAMP-2 and in turn, overexpression of LAMP-2 caused a reduction in secreted levels of Aβ1-42, as well as changing the generation pattern of Aβ and affecting clearance and secretion of Aβ1-42. These data indicate that the increased levels of LAMP-2 in AD could be an attempt to regulate Aβ generation and secretion.

In summary, this thesis reports that utilising lysosomal network proteins as biomarkers and novel therapeutic targets for neurodegenerative diseases holds great promise.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 58 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1492
Keyword
Cerebrospinal fluid (CSF), biomarkers, therapeutic targets, neurodegeneration, Alzheimer’s disease (AD), Parkinson’s disease (PD), Corticobasal degeneration (CBD), Progressive supraneuclear palsy (PSP), Lysosomes, Endosomes, Autophagy, LAMP-2, Lysozyme
National Category
Neurosciences Neurology Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-122347 (URN)10.3384/diss.diva-122347 (DOI)978-91-7685-897-4 (print) (ISBN)
Public defence
2015-11-26, Eken, Campus US, Linköping, 09:00 (Swedish)
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Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2015-10-30Bibliographically approved

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