20 | Exercise preserves purkinje cells' integrity from paraneoplastic cerebellar degeneration in a mouse model of cachexia

Francesco Paolo Zummo, V. Sagagandomabadi, R. Barone, F. Macaluso, D. D'Amico, M. Sausa, F. Carini, V. Di Felice, S. David | Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Italy.

Abstract

Paraneoplastic syndromes are secondary conditions to the systemic effects of cancer. Among these, cancer cachexia is highly prevalent and characterized by weight loss and muscle wasting, while paraneoplastic cerebellar degeneration (PCD), defined by immune-mediated damage to Purkinje cells, is one of the most common neurological forms. Although exercise has been suggested as a strategy to counteract cachexia, the impact of training in PCD has not yet been investigated. In this study, we combined a C26 mouse model with an endurance protocol to explore the exercise effects on Purkinje cells in sedentary (SED T+) and trained (TR T+) tumour groups compared to sedentary (SED T−) and trained (TR T−) non-tumour groups. Cachexia onset was confirmed through body weight and strength loss analyses. Even if histological analysis revealed that the cerebellar area was similar across groups, Purkinje cell body circularity index and layer thickness were significantly reduced in SED T+ mice and restored in TR T+ animals. Since ZIC4 is one of the transcription factors affected by the autoimmune response in PCD, we evaluated its expression and localization both in immunohistochemistry and immunofluorescence. ZIC4 expression was reduced in SED T+ mice, but training was able to protect Purkinje cells from any autoimmune attack during tumour development. We also assessed the expression of PSD95, a common marker used for the immunolabeling of the post-synaptic side of excitatory synapses. The very low expression of the PSD95 protein in SED T+ mice suggested that the tumour mass affected the synaptic plasticity, while training again preserved synapses from the devastating effects of the tumour circulating factors. Altogether, these results suggest an important role of training in the protection of cerebellum damage. Further studies are needed to clarify the role of exercise in protecting the stimulating synapses of the efferent fibers of the cerebellar cortex.