Nigral injection of a proteasomal inhibitor, lactacystin, induces widespread glial cell activation and shows various phenotypes of Parkinson's disease in young and adult mouse

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Savolainen , M H , Albert , K , Airavaara , M & Myohänen , T T 2017 , ' Nigral injection of a proteasomal inhibitor, lactacystin, induces widespread glial cell activation and shows various phenotypes of Parkinson's disease in young and adult mouse ' , Experimental Brain Research , vol. 235 , no. 7 , pp. 2189-2202 . https://doi.org/10.1007/s00221-017-4962-z

Title: Nigral injection of a proteasomal inhibitor, lactacystin, induces widespread glial cell activation and shows various phenotypes of Parkinson's disease in young and adult mouse
Author: Savolainen, Mari H.; Albert, Katrina; Airavaara, Mikko; Myohänen, Timo T.
Contributor organization: Faculty of Pharmacy
Division of Pharmacology and Pharmacotherapy
Regenerative pharmacology group
University of Helsinki
Institute of Biotechnology
Drug Research Program
Regenerative Neuroscience
PREP in neurodegenerative disorders
Date: 2017-07
Language: eng
Number of pages: 14
Belongs to series: Experimental Brain Research
ISSN: 0014-4819
DOI: https://doi.org/10.1007/s00221-017-4962-z
URI: http://hdl.handle.net/10138/307681
Abstract: Proteinaceous inclusions, called Lewy bodies, are used as a pathological hallmark for Parkinson's disease (PD). Lewy bodies contain insoluble alpha-synuclein (aSyn) and many other ubiquitinated proteins, suggesting a role for protein degradation system failure in the PD pathogenesis. Indeed, proteasomal dysfunction has been linked to PD but commonly used in vivo toxin models, such as 6-OHDA or MPTP, do not have a significant effect on the proteasomal system or protein aggregation. Therefore, we wanted to study the characteristics of a proteasomal inhibitor, lactacystin, as a PD model on young and adult mice. To study this, we performed stereotactic microinjection of lactacystin above the substantia nigra pars compacta in young (2 month old) and adult (12-14 month old) C57Bl/6 mice. Motor behavior was measured by locomotor activity and cylinder tests, and the markers of neuroinflammation, aSyn, and dopaminergic system were assessed by immunohistochemistry and HPLC. We found that lactacystin induced a Parkinson's disease-like motor phenotype 5-7 days after injection in young and adult mice, and this was associated with widespread neuroinflammation based on glial cell markers, aSyn accumulation in substantia nigra, striatal dopamine decrease, and loss of dopaminergic cell bodies in the substantia nigra and terminals in the striatum. When comparing young and adult mice, adult mice were more sensitive for dopaminergic degeneration after lactacystin injection that further supports the use of adult mice instead of young when modeling neurodegeneration. Our data showed that lactacystin is useful in modeling various aspects of Parkinson's disease, and taken together, our findings emphasize the role of a protein degradation deficit in Parkinson's disease pathology, and support the use of proteasomal inhibitors as Parkinson's disease models.
Subject: Ubiquitin-proteasome system
Proteasome inhibition
Neuroinflammation
Neurodegeneration
Preclinical models
Alpha-synuclein
MULTIPLE SYSTEM ATROPHY
ALPHA-SYNUCLEIN
SUBSTANTIA-NIGRA
IN-VIVO
LEWY BODIES
FILAMENTOUS INCLUSIONS
MICROGLIAL ACTIVATION
TYROSINE-HYDROXYLASE
BASAL GANGLIA
UP-REGULATION
3112 Neurosciences
Peer reviewed: Yes
Rights: unspecified
Usage restriction: openAccess
Self-archived version: acceptedVersion


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