Different Purkinje cell pathologies cause specific patterns of progressive gait ataxia in mice

Neurobiol Dis. 2024 Jan 28;192:106422. doi: 10.1016/j.nbd.2024.106422. Online ahead of print.ABSTRACTGait ataxia is one of the most common and impactful consequences of cerebellar dysfunction. Purkinje cells, the sole output neurons of the cerebellar cortex, are often involved in the underlying pathology, but their specific functions during locomotor control in health and disease remain obfuscated. We aimed to describe the effect of gradual adult-onset Purkinje cell degeneration on gaiting patterns in mice, and to determine whether two different mechanisms that both lead to Purkinje cell degeneration cause different patterns in the development of gait ataxia. Using the ErasmusLadder together with a newly developed limb detection algorithm and machine learning-based classification, we subjected mice to a challenging locomotor task with detailed analysis of single limb parameters, intralimb coordination and whole-body movement. We tested two Purkinje cell-specific mouse models, one involving stochastic cell death due to impaired DNA repair mechanisms (Pcp2-Ercc1-/-), the other carrying the mutation that causes spinocerebellar ataxia type 1 (Pcp2-ATXN1[82Q]). Both mouse models showed progressive gaiting deficits, but the sequence with which gaiting parameters deteriorated was different between mouse lines. Our longitudinal approach revealed that gradual loss of Purkinje cell function can lead to a complex pattern of loss of function over time, and that this pattern depends on th...
Source: Neurobiology of Disease - Category: Neurology Authors: Source Type: research