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JPND-EU Joint Programme - Neurodege

Early indicators of nervous system dysfunction in gut-first and brain-first animal models of Parkinson’s Disease

Alternative title: Tidlige indikatorer av dysfunskjonalitet i neurala systemer for mage og hjerne initiert Parkinson sykedom

Awarded: NOK 2.3 mill.

Parkinson’s disease (PD) is usually characterized by alphasynuclein aggregates, also known as Lewy pathology. This is similar to e.g., Alzheimers disease, but the proteins involved are different. The spread of these aggregates through synapses is believed to be a crucial pathogenic factor. PD pathology is not just in the central nervous system (CNS), but in multiple peripheral organs as well. For example, aggregates have been found in gut tissue of PD patients and symptoms of gut dysfunction, such as constipation can appear up to 20 years before parkinsonian motor symptoms. These findings all support the gut-first hypothesis of PD pathogenesis, so that the pathological conversion of endogenous aggregates originates in the gut and spreads to the brain. Nevertheless, evidence from neuropathological studies suggests that not all PD patients conform to the gut-first hypothesis. In short, we propose that disease heterogeneity can be explained in part by dividing PD into a body-first subtype where asyn pathology arises in the body and spreads to the brain, and a brain-first subtype where asyn pathology arises in the brain and spreads to the body. Ultimately, both disease subtypes will evolve to a similar advanced disease stage over time where the entire brain and several peripheral organs are affected. In the project a variety of biomarkers and novel fluorescent probes will be used to study PD in animal and cell models to elucidate on the various mechanisms for disease onset and spread.

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. 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. Synthesizing and using novel fluorescent ligands we will stain misfolded asyn to enable studies of early 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 immunohistochemical analysis. 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. The results will guide in translational research to stratify PD subtypes at early disease stages allowing personalized and disease-modifying treatment.

Funding scheme:

JPND-EU Joint Programme - Neurodege