Abstract
Chorea acanthocytosis (ChAc), an ultra-rare devastating neurodegenerative disease, is caused by mutations in the VPS13A gene, which encodes for the protein chorein. Affected patients suffer from chorea, orofacial dyskinesia, epilepsy, parkinsonism as well as peripheral neuropathy. Although medium spinal neurons of the striatum are mainly affected, other regions are impaired as well over the course of the disease. Animal studies as well as studies on human erythrocytes suggest Lyn-kinase inhibition as valuable novel opportunity to treat ChAc. In order to investigate the peripheral neuropathy aspect, we analyzed induced pluripotent stem cell derived midbrain/hindbrain cell cultures from ChAc patients in vitro. We observed dendritic microtubule fragmentation. Furthermore, by using in vitro live cell imaging, we found a reduction in the number of lysosomes and mitochondria, shortened mitochondria, an increase in retrograde transport and hyperpolarization as measured with the fluorescent probe JC-1. Deep phenotyping pointed towards a proximal axonal deterioration as the primary axonal disease phenotype. Interestingly, pharmacological interventions, which proved to be successful in different models of ChAc, were ineffective in treating the observed axonal phenotypes. Our data suggests that treatment of this multifaceted disease might be cell type and/or neuronal subtype specific, and thus necessitates precision medicine in this ultra-rare disease.
Highlights
Chorea Acanthocytosis (ChAc) is a rare neurodegenerative disease that affects 500–1000 persons worldwide (OMIM ID: 200150) [1]
Since peripheral neuropathy is a main symptom of ChAc patients, which is helpful to distinguish it from diseases such as Huntington’s disease, we looked for neurite outgrowth of individual neurons within the first 72 h after seeding following the neuronal induction
The main focus of the scientific community lies on the investigation of erythrocyte and medium spiny neuron (MSN) phenotypes as the primarily affected cell types
Summary
Chorea Acanthocytosis (ChAc) is a rare neurodegenerative disease that affects 500–1000 persons worldwide (OMIM ID: 200150) [1]. It is part of the group of neuroacanthocytosis syndromes, which include McLeod syndrome, Huntington disease-like syndrome 2 and pantothenate kinase-associated neurodegeneration. Patients affected by the disease present various clinical features including orofacial dyskinesia and choreatiform movements with typical drops of the upper body. The affected neurons mainly responsible for the choreatiform movement disorder are medium spiny neurons (MSN) of the basal ganglia [3]. Many other neuronal subtypes are affected as well, such as dopaminergic neurons or motoneurons, explaining the plethora of maladies including parkinsonism and/or peripheral neuropathy [4]
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