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Chorea-acanthocytosis (ChAc) is a neurodegenerative disease caused by mutations in the VPS13A gene. It is characterized by several neurological symptoms and the appearance of acanthocytes. Elevated tyrosine kinase Lyn activity has been recently identified as one of the key pathophysiological mechanisms in this disease, and therefore represents a promising drug target. Methods: We evaluated an individual off-label treatment with the tyrosine kinase inhibitor dasatinib (100 mg/d, 25.8–50.4 weeks) of three ChAc patients. Alongside thorough safety monitoring, we assessed motor and non-motor scales (e.g., MDS-UPDRS, UHDRS, quality of life) as well as routine and experimental laboratory parameters (e.g., serum neurofilament, Lyn kinase activity, actin cytoskeleton in red blood cells). Results: Dasatinib appeared to be reasonably safe. The clinical parameters remained stable without significant improvement or deterioration. Regain of deep tendon reflexes was observed in one patient. Creatine kinase, serum neurofilament levels, and acanthocyte count did not reveal consistent effects. However, a reduction of initially elevated Lyn kinase activity and accumulated autophagy markers, as well as a partial restoration of the actin cytoskeleton, was found in red blood cells. Conclusions: We report on the first treatment approach with disease-modifying intention in ChAc. The experimental parameters indicate target engagement in red blood cells, while clinical effects on the central nervous system could not be proven within a rather short treatment time. Limited knowledge on the natural history of ChAc and the lack of appropriate biomarkers remain major barriers for “clinical trial readiness”. We suggest a panel of outcome parameters for future clinical trials in ChAc.

Gα i2, a heterotrimeric G‐protein subunit, regulates various cell functions including ion channel activity, cell differentiation, proliferation and apoptosis. Platelet‐expressed Gα i2 is decisive for the extent of tissue injury following ischemia/reperfusion. However, it is not known whether Gα i2 plays a role in the regulation of platelet apoptosis, which is characterized by caspase activation, cell shrinkage and cell membrane scrambling with phosphatidylserine (PS) translocation to the platelet surface. Stimulators of platelet apoptosis include thrombin and collagen‐related peptide (CoRP), which are further known to enhance degranulation and activation of α II b β3‐integrin and caspases. Using FACS analysis, we examined the impact of agonist treatment on activation and apoptosis in platelets drawn from mice lacking Gα i2 and their wild‐type (WT) littermates. As a result, treatment with either thrombin (0.01 U/mL) or CoRP (2 μg/mL or 5 μg/mL) significantly upregulated PS‐exposure and significantly decreased forward scatter, reflecting cell size, in both genotypes. Exposure to CoRP triggered a significant increase in active caspase 3, ceramide formation, surface P‐selectin, and α II b β3‐integrin activation. These molecular alterations were significantly less pronounced in Gα i2‐deficient platelets as compared to WT platelets. In conclusion, our data highlight a previously unreported role of Gα i2 signaling in governing platelet activation and apoptosis.

Fil: Cao, Hang. Eberhard-Karls University. Department of Vegetative & Clinical Physiology; Alemania Fil: Qadri, Syed M. McMaster University. Department of Pathology and Molecular Medicine; Canadá Fil: Qadri, Syed M. Canadian Blood Services. Centre for Innovation Fil: Lang, Elisabeth. Heinrich Heine University. Department of Molecular Medicine II; Alemania Fil: Pelzl, Lisann. Eberhard-Karls University. Department of Vegetative & Clinical Physiology; Alemania Fil: Umbach, Anja T. Eberhard-Karls University. Department of Vegetative & Clinical Physiology; Alemania Fil: Leiss, Veronika. Eberhard-Karls University. Interfaculty Center of Pharmacology and Drug Research. Department of Pharmacology and Experimental Therapy; Alemania Fil: Birnbaumer, Lutz. Research Triangle Park. National Institute of Environmental Health Sciences. Neurobiology Laboratory; Estados Unidos Fil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Nürnberg, Bernd. Eberhard-Karls University. Interfaculty Center of Pharmacology and Drug Research. Department of Pharmacology and Experimental Therapy; Alemania Fil: Pieske, Burkert. Charite-Universitätsmedizin Berlin. Department of Internal Medicine and Cardiology; Alemania Fil: Pieske, Burkert. Berlin Institute of Health; Alemania Fil: Pieske, Burkert. German Centre for Cardiovascular Research; Alemania Fil: Voelkl, Jakob. Charite-Universitätsmedizin Berlin. Department of Internal Medicine and Cardiology; Alemania Fil: Voelkl, Jakob. Berlin Institute of Health; Alemania Fil: Voelkl, Jakob. Charite-Universitätsmedizin Berlin. Department of Internal Medicine and Cardiology; Alemania Fil: Gawaz, Meinrad. Eberhard-Karls University. Department of Internal Medicine III; Alemania Fil: Bissinger, Rosi. Eberhard-Karls University. Department of Internal Medicine III; Alemania Fil: Lang, Florian. Eberhard-Karls University. Department of Vegetative & Clinical Physiology; Alemania Fil: Lang, Florian. Heinrich Heine University. Department of Molecular Medicine II; Alemania Abstract: Gαi2 , a heterotrimeric G-protein subunit, regulates various cell functions including ion channel activity, cell differentiation, proliferation and apoptosis. Platelet-expressed Gαi2 is decisive for the extent of tissue injury following ischemia/reperfusion. However, it is not known whether Gαi2 plays a role in the regulation of platelet apoptosis, which is characterized by caspase activation, cell shrinkage and cell membrane scrambling with phosphatidylserine (PS) translocation to the platelet surface. Stimulators of platelet apoptosis include thrombin and collagen-related peptide (CoRP), which are further known to enhance degranulation and activation of αIIb β3-integrin and caspases. Using FACS analysis, we examined the impact of agonist treatment on activation and apoptosis in platelets drawn from mice lacking Gαi2 and their wild-type (WT) littermates. As a result, treatment with either thrombin (0.01 U/mL) or CoRP (2 μg/mL or 5 μg/mL) significantly upregulated PS-exposure and significantly decreased forward scatter, reflecting cell size, in both genotypes. Exposure to CoRP triggered a significant increase in active caspase 3, ceramide formation, surface P-selectin, and αIIb β3-integrin activation. These molecular alterations were significantly less pronounced in Gαi2 -deficient platelets as compared to WT platelets. In conclusion, our data highlight a previously unreported role of Gαi2 signaling in governing platelet activation and apoptosis.