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Start of funding 01.07.2020
Myeloid cell depletion as therapeutic target in multiple system atrophy
Dr. Alana Hoffmann
Friedrich-Alexander-University of Erlangen-Nuremberg
Division of Molecular Neurology
Prof. Dr. Robert Rissmann
University of California, San Diego
Department of Neurosciences
Multiple system atrophy (MSA) is an orphan atypical parkinsonian syndrome characterized by a malignant, aggressive, and rapid disease progression. Since there is no therapy available to modify disease progression, there is an urgent need for disease modifying therapeutic approaches. MSA neuropathology is accompanied by profound microgliosis. Using human post-mortem brain tissue of MSA patients and a mouse model representing important neuropathological features of MSA, we aim to characterize microglia immune responses and their contribution to disease pathogenesis. In addition, the impact on microglia depletion will be analyzed in the respective preclinical model.
Final report:
Together with the Departments of Neuroscience and Cellular and Molecular Medicine at the University of California, San Diego, we investigated the role of CNS myeloid cells in a mouse model of multiple system atrophy. Using a specific depletion approach, we reduced the number of myeloid cells in the brain of transgenic mice which modified the neuropathology and behavioral phenotype of these animals. Interestingly, depletion of myeloid cells improved the survival, delayed the onset of disease and reduced inflammatory responses. On the contrary, motor function was deteriorated and synaptic signaling as well as neuronal circuits were affected in transgenic animals lacking myeloid cells. We published the results of our collaboration last year in the Journal of Neuroscience (Battis K, Florio JB, Mante M, Lana A, Naumann I, Gauer C, Lambrecht V, Müller SJ, Cobo I, Fixsen B, Kim HY, Masliah E, Glass CK, Schlachetzki JCM, Rissman RA, Winkler J, Hoffmann A. CSF1R-Mediated Myeloid Cell Depletion Prolongs Lifespan But Aggravates Distinct Motor Symptoms in a Model of Multiple System Atrophy. J Neurosci. 2022; PMID: 36333098). Overall, this study unraveled a complex role of myeloid cells in multiple system atrophy which further emphasizes the need to understand and fine-tune immune processes in neurodegenerative disease. We are in close contact and lively exchange with the groups at UCSD to continue our collaboration to understand the role of myeloid cells in the pathogenesis of multiple system atrophy and to use them as target for novel therapeutic approaches.