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Project Topic
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Parkinson's disease (PD) is characterized by pathological misfolding of the protein alpha-synuclein (asyn),
which causes progressive neurodegeneration in the brain and subsequent motor symptoms. The spread of
pathogenic asyn bidirectionally and trans-synaptically along the body-brain axis is believed to be a crucial pathogenic
factor in PD. Next to a damaged brain, it is well-known that PD patients exhibit extensive nerve damage to peripheral
organs, such as in the heart and the gut, causing debilitating non-motor symptoms up to 20 years before the motor
symptoms occur. This early ‘pre-motor´ disease phase is highly heterogeneous across patients with variable
involvement of different neuronal systems. It is conceivable that the large variability in early disease phenotype could
be attributed to the variability in disease initiation, i.e. body or brain. In our recently published imaging study of human
patients, we hypothesized that PD can be divided in two subtypes: (1) a body-first type, where damage to the cardiac
and enteric nervous system precedes damage to the brain, and (2) a brain-first type where neuronal loss in the brain
precedes nerve damage to other organs. To date, no cure is available for PD and therapy is limited to symptomatic
treatment of motor symptoms. Thus, it is crucial to establish animal models with a clear pre-motor phase (i.e.
therapeutic window) that resemble human PD subtypes, which will allow testing of personalized treatment
strategies per subtype. Here, we will emulate the two types of PD as observed in humans by injecting pathogenic
asyn in the gut (= body-first) vs. in the amygdala (= brain-first) of transgenic or old wild-type mice. We will map the
spatio-temporal spread of pathogenic asyn and progressive neuronal dysfunction from the initiation, via early disease
stages to late disease stages, using a broad battery of in vivo and ex vivo techniques such as longitudinal in vivo
functional imaging, autoradiography, symptom scoring, and thorough immunohistochemical analysis. We expect to
show that these two animal models closely parallel observations in human patients with early involvement of the
peripheral autonomic nervous system in body-first PD (i.e. as in isolated REM sleep behavior disorder patients)
as opposed to brain-first PD, where peripheral organs are relatively spared at early disease stages. Besides
asyn propagation and neuronal dysfunction, we aim to assess other cardinal features of PD pathogenesis in our
models, such as reactive astrogliosis and lysosomal dysfunction. These pathogenic processes are reported to
precede the formation of asyn pathology and neurodegeneration and could be suitable early disease indicators.
Finally, we hypothesize that the phenotypic and histopathological variability between body-first and brain-first PD
could result, apart from the different disease initiation site, from variation in the intrinsic structure of the asyn
aggregates. The strain hypothesis in synucleinopathies postulates that each disease entity is characterized by a
distinct conformation of pathogenic asyn, therefore, each PD subtype could be caused by a unique asyn structure or
strain. In order to investigate this hypothesis, we will use a panel of thiophene-based ligands that produce a ‘spectral
fingerprint’ of protein aggregates upon interaction. This interaction will be studied using cell models as well as tissue
sections or biofluids. The identification of subtype-specific asyn aggregates in easily accessible peripheral
fluids or tissues from our body-first or brain-first animals may enable stratification in different PD subtypes. Positive
results will have important implications in translational research to stratify PD subtypes at early disease stages
allowing personalized and disease-modifying treatment. Especially in the body-first PD subtype, where damage to
the brain is limited at the early stage, early diagnosis would create a large therapeutic window. Thus, particularly for
body-first PD, the identification of early disease biomarkers such as autonomic dysfunction, inflammation,
lysosomal dysfunction and/or unique intrinsic asyn structure are beneficial as it would allow early therapeutic
intervention. Thus, this project may contribute significantly to the development of early disease biomarkers and
disease-modifying treatment targets.
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