The proteasome inhibition mouse model of Parkinson's disease: insights into molecular and behavioral changes following intranigral lactacystin injection
Eduard
Bentea1*,
Anke
Van Der Perren2,
Joeri
Van Liefferinge1,
Michelle
Sconce3,
Madeline
Churchill3,
Rebecca
Hood3,
Lauren
Deneyer1,
Anissa
El Arfani1,
Giulia
Albertini1,
Thomas
Demuyser1,
Ellen
Merckx1,
Ilse
Smolders1,
Charles
Meshul3,
Veerle
Baekelandt2 and
Ann
Massie1
-
1
Vrije Universiteit Brussel, Center for Neurosciences, Belgium
-
2
KU Leuven, Department of Neurosciences, Belgium
-
3
Oregon Health & Science University, Department of Behavioral Neuroscience, United States
In Parkinson's disease (PD), the progressive degeneration of the nigrostriatal dopamine (DA) pathway leads to loss of striatal DA content, dysregulation of the basal ganglia motor circuit, and inhibition of movement. In addition, PD patients present with non-motor symptoms that can be debilitating in terms of impact on quality of life. From a molecular perspective, various factors have been implicated in the loss of DA neurons in PD, including failure of protein degradation pathways leading to aberrant protein accumulation. The aim of the current study was to evaluate molecular and behavioral abnormalities in a mouse model of PD, based on the intranigral infusion of proteasome inhibitor lactacystin (LAC). C57BL/6J mice, 12 weeks of age, were stereotaxically injected with 3 µg LAC or saline in the left substantia nigra pars compacta. One or three weeks following surgery, mice were tested in various behavioral paradigms, and brain tissue further processed for evaluating molecular and neurodegenerative changes. Our findings demonstrate that LAC-treated mice show loss of nigral DA-ergic neurons and concurrent striatal DA depletion, and develop behavioral (motor and non-motor) deficits, including impaired motor coordination and balance, motor asymmetry, hyperactivity, anxiety-like behavior, somatosensory dysfunction, and response perseveration. Furthermore, LAC infusion led to accumulation of Ser129-phosphorylated α-synuclein and increased VGLUT2 immunoreactivity in the ipsilateral substantia nigra. Our findings indicate that mice treated with proteasome inhibitor LAC develop parkinsonian features, including motor and non-motor impairment, pathological α-synuclein accumulation, and glutamatergic dysfunction that could be linked with increased activity of the subthalamic nucleus.
Keywords:
mouse model,
Parkinson Disease,
Proteasome,
Behavior,
alpha-Synuclein,
VGLUT2
Conference:
11th National Congress of the Belgian Society for Neuroscience, Mons, Belgium, 22 May - 22 May, 2015.
Presentation Type:
Oral or Poster presentation
Topic:
Neuroscience
Citation:
Bentea
E,
Van Der Perren
A,
Van Liefferinge
J,
Sconce
M,
Churchill
M,
Hood
R,
Deneyer
L,
El Arfani
A,
Albertini
G,
Demuyser
T,
Merckx
E,
Smolders
I,
Meshul
C,
Baekelandt
V and
Massie
A
(2015). The proteasome inhibition mouse model of Parkinson's disease: insights into molecular and behavioral changes following intranigral lactacystin injection.
Front. Neurosci.
Conference Abstract:
11th National Congress of the Belgian Society for Neuroscience.
doi: 10.3389/conf.fnins.2015.89.00051
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Received:
29 Apr 2015;
Published Online:
05 May 2015.
*
Correspondence:
Mr. Eduard Bentea, Vrije Universiteit Brussel, Center for Neurosciences, Brussels, Belgium, ebentea@yahoo.com