Metabolic Changes in Neurodegeneration

apl. Prof. Dr. Dr. Francesco Roselli

Areas of investigation/research focus

Hypothalamus is the structure of the brain responsible for the maintenance of  the homeostasis of the body, i.e. for keeping in equilibrium a number of biological functions and parameters necessary for the biochemical integrity of the body (e.g., the balance of ions or the blood pressure), for the energy balance (regulating food intake and energy expenditure) and regulation of stress and reproduction. Dysfunctions of hypothalamus are only now recognized to be part of the spectrum of manifestations of several neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS) and Huntington Disease (HD), in which body metabolism is disrupted early on in disease progression and in which the progressive  wasting is a major feature associated with accelerated progression and shorter survival. But why it is so? Hypothalamic neurons, which come in large variety and different neurochemical identities, are not traditional targets of neurodegeneration, in contrast to motoneurons in ALS or striatal neurons in HD. But is it really so? Are there more changes unfolding in the hypothalamus in neurodegenerative disorders than we have already found? And even if the hypothalamus per se may be not affected, it receives projections from a large fraction of the brain and projects to almost every structure in the brain: may the disruption of the connections of the hypothalamus be disrupted in disease, leading to the energy imbalance and disturbances in food intake seen in neurodegenerative diseases? On the other hand, are interventions at hypothalamic level able to affect the vulnerability and loss of other neuronal populations?

We employ a set of multiple approaches to unravel the contribution of hypothalamus to neurodegenerative diseases and the impact of neurodegeneration on hypothalamic function. We exploit state-of-the-art viral vectors, and we develop new ones, to delineate the two-ways connections between hypothalamic nuclei and the rest of the brain in ALS mouse models characterized by more or less pronounced metabolic phenotypes. We use then artificial intelligence approaches to identify and locate each neuron in the mouse brain projecting to a given hypothalamic nucleus, so that differences in projections can be mapped over time.

We also use chemogenetic and multiplexed chemogenetic approaches to activate or de-activate selected neuronal subpopulation to verify their impact on the overall metabolic phenotypes in murine models of ALS, each carrying mutations in one of several disease-related genes (FUS, TDP-43, SOD1 and others). We aim at identifying which neuronal subpopulation needs to be re-activated to compensate the energy balance dysfunction and see if this approach has beneficial effects on disease progression.

Independently, we are using antibody arrays to characterize the neurochemical changes that appear in the hypothalamus of ALS murine models before and after the onset of the disease. This approach has already revealed several new peptide mediators involved in energy homeostasis in disease. In our translational efforts, we analyze biological samples (blood, cerebrospinal fluid) from patients with ALS to verify that the neuropeptides we have identified in the murine models are also altered in humans and therefore may serve as new biomarkers of hypothalamic dysfunction and disease progression.

Finally, we are involved in the effort to use metabolism manipulations as therapeutic approach for neurodegeneration: high-energy dietary supplements are being tested in clinical trials to determine their impact on survival, disease progression and neurochemical dysfunctions.

Welcome to our website, here you can inform yourself basically cookie-free.

We would be pleased if you would allow a cookie to be set for analysis purposes in order to optimise our provided information. All data are pseudonymous and are only used by the DZNE. We deliberately avoid third-party cookies. You can deselect this setting at any time here.

Your browser allows the setting of cookies: