Francesco Roselli
Metabolic Changes in Neurodegeneration
apl. Prof. Dr. Dr. Francesco Roselli
Group Leader
c/o Center for Biomedical Research R1.44
Helmholtzstraße 8/2
89081  Ulm
 +49 731 50063147

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?

 more Infos

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.

Key publications

Bączyk M, Alami NO, Delestrée N, Martinot C, Tang L, Commisso B, Bayer D, Doisne N, Frankel W, Manuel M, Roselli F, Zytnicki D. Synaptic restoration by cAMP/PKA drives activity-dependent neuroprotection to motoneurons in ALS. J Exp Med. 2020 Jan 01; doi: jem.20191734
Ludolph AC, Dorst J, Dreyhaupt J, Weishaupt JH, Kassubek J, Weiland U, Meyer T, Petri S, Hermann A, Emmer A, Grosskreutz J, Grehl T, Zeller D, Boentert M, Schrank B, Prudlo J, Winkler AS, Gorbulev S, Roselli F, Schuster J, Dupuis L; LIPCAL-ALS Study Group. Effect of High-Caloric Nutrition on Survival in Amyotrophic Lateral Sclerosis. Ann Neurol. 2020 Feb 01; 87:206-216. doi: 10.1002/ana.25661
Catanese A, Olde Heuvel F, Mulaw M, Demestre M, Higelin J, Barbi G, Freischmidt A, Weishaupt JH, Ludolph AC, *Roselli F, *Boeckers TM. *co-senior authors. Retinoic acid worsens ATG10-dependent autophagy impairment in TBK1-mutant hiPSC-derived motoneurons through SQSTM1/p62 accumulation. Autophagy. 2019 Oct 01; 15:1719-1737. doi: 10.1080/15548627.2019.1589257
Commisso B, Ding L, Varadi K, Gorges M, Bayer D, Boeckers TM, Ludolph AC, Kassubek J, Müller OJ, Roselli F. Stage-dependent remodeling of projections to motor cortex in ALS mouse model revealed by a new variant retrogradeStage-dependent remodeling of projections to motor cortex in ALS mouse model revealed by a new variant retrograde-AAV9-AAV9. Elife. 2018 Aug 23; 7:pii: e36892. doi: 10.7554/eLife.36892
Ouali Alami N, Schurr C, Olde Heuvel F, Tang L, Li Q, Tasdogan A, Kimbara A, Nettekoven M, Ottaviani G, Raposo C, Röver S, Rogers-Evans M, Rothenhäusler B, Ullmer C, Fingerle J, Grether U, Knuesel I, Boeckers TM, Ludolph A, Wirth T, *Roselli F, *Baumann B. *co-senior authors. NF-κB activation in astrocytes drives a stage-specific beneficial neuroimmunological response in ALS. EMBO J. 2018 Aug 15; 37:pii: e98697. doi: 10.15252/embj.201798697


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