2016 Scientific Report

We also use mouse models to evaluate α-syn transmission
between brain regions. In one model, mice are first
engineered to express large amounts of human α-syn
protein in the nigrostriatal pathway. Immature neurons
lacking human α-syn (graft) are transplanted into the
striatum. After several weeks, human α-syn can be found
in the transplanted neurons, which could only occur by
transmission from the host brain to the grafted neurons.
We are currently defining how inflammation contributes to
α-syn spread in this model. We hypothesize that microglia
remove extracellular α-syn that is available for transfer from
cell to cell, and that the activation of microglia (as occurs in
PD) will influence the efficacy of clearance of α-syn from the
extracellular space.
We have developed another mouse model based on
injections of misfolded α-syn into the olfactory bulb. The
loss of olfaction is an early change in PD, and the olfactory
bulb has been proposed to be a starting point of Lewy body
pathology, possibly due to an environmental insult. In our
model, α-syn aggregate pathology gradually spreads along
olfactory pathways, causing progressive olfactory deficits.
Given that α-syn transmission between cells is thought to
drive PD progression, interfering with this process might
slow the worsening of symptoms. We have partnered with
GISMO Therapeutics Inc. and obtained funding from the
Michael J. Fox Foundation to evaluate the ability of heparan
sulfate proteoglycan (HSPG) inhibitors to prevent transfer of
α-syn between cells in cell culture and in mouse models.
Genetic factors other than α-syn also influence PD
risk. Recent genetic studies have identified the enzyme
aminocarboxy-muconate semialdehyde decarboxylase
(ACMSD) as a modifier of PD risk. This enzyme is a key
regulator of the kynurenine pathway, which regulates
neuroinflammation. The Michael J. Fox Foundation funds a
joint project with Dr. Lena Brundin in which we are exploring
whether overexpression of ACMSD in a rat model of PD can
reduce neuroinflammation and be neuroprotective.
We are also exploring whether modulation of the
mitochondrial pyruvate carrier (MPC) can protect neurons
from death. We use the compound MSDC-0160, which is
an MPC modulator originally developed as an anti-diabetic
agent. Thanks to funding from the Cure Parkinson’s Trust
UK, the Campbell Foundation, and the Spica family, we
have shown that MSDC-0160 is a powerful protectant
against neurodegeneration in several toxin and genetic
models of PD. The compound influences the capacity
of the neurons to carry out the autophagy process (a cell
stress response that is altered in PD), promoting their
survival, and it also inhibits neuroinflammation. Given the
favorable safety profile of MSDC-0160, the drug is already
under consideration for PD clinical trials, demonstrating its
high potential for clinical translation.
RECENT PUBLICATIONS
Brundin, Patrik, Graham Atkin, and Jennifer T. Lamberts. 2015. Basic science breaks through: new therapeutic advances in
Parkinson’s disease. Movement Disorders 30(11): 1521–1527.
Nordström, Ulrika, Geneviève Beauvais, Anamitra Ghosh, Baby Chakrapani Pulikkaparambil Sasidharan, Martin Lundblad,
Julia Fuchs, Rajiv L. Joshi, Jack W. Lipton, Andrew Roholt, et al. 2015. Progressive nigrostriatal terminal dysfunction and
degeneration in the engrailed1 heterozygous mouse model of Parkinson’s disease. Neurobiology of Disease 73: 70–82.
Reyes, Juan F., Tomas T. Olsson, Jennifer T. Lamberts, Michael J. Devine, Tilo Kunath, and Patrik Brundin. 2015. A cell culture
model for monitoring α-synuclein cell-to-cell transfer. Neurobiology of Disease 77: 266–275.
CENTER FOR NEURODEGENERATIVE SCIENCE
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