Establishment of spinocerebellar ataxia type 34 model mice accompanied by early glial activation and degeneration of cerebellar neurons

Spinocerebellar ataxia type 34 (SCA34) is an autosomal dominant neurodegenerative disease primarily characterized by progressive cerebellar atrophy and ataxia, frequently accompanied by cognitive dysfunction and erythrokeratodermia variabilis. SCA34 is caused by missense mutations of elongation of very long chain fatty acids protein 4 (ELOVL4). To investigate its pathogenesis, we established an SCA34 mouse model by expressing mutant ELOVL4 in cerebellar neurons using adeno-associated virus vectors. Expression of W246G mutant ELOVL4 successfully induced progressive motor dysfunction beginning at two weeks post-injection. Immunohistochemical analyses revealed that the loss of cerebellar Purkinje cells and neurons in the deep cerebellar nuclei (DCN) paralleled the observed motor decline. Importantly, microglial activation was detected in the molecular layer of the cerebellar cortices and the DCN prior to the loss of cerebellar neurons and the onset of motor dysfunction. Furthermore, after the onset of motor symptoms, the SCA34 model mice exhibited decreased expression of presynaptic proteins in climbing fibers to Purkinje cells, as well as disturbance of innervation from Purkinje cells to DCN neurons. These findings suggest that early microglial activation and the resulting synaptic disturbance are critical preceding events that lead to the progressive cerebellar neurodegeneration and motor dysfunction observed in this SCA34 mouse model.