Elucidating mechanisms of patterned Purkinje cell loss in Christianson syndrome ataxia

An intriguing phenomenon occurs in many neurodegenerative diseases, where sub-populations of the same type of neurons have widely different responses to the same genetic insult: some survive, while others die. In the mammalian brain, one of the most vulnerable neuronal cell types are cerebellar Purkinje cells (PCs). In cerebellar ataxia, a motor coordination disorder characterized by cerebellar degeneration, PCs often show differential regional vulnerability. The mechanisms underpinning this selective neuronal vulnerability remain unclear but offer great promise for development of novel therapeutic approaches that tap into mechanisms of resilience across the mammalian brain. A characteristic pattern of anterior lobe cerebellar degeneration has been observed in several ataxias, including Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and Christianson syndrome (CS). To better understand this differential PC vulnerability, it is important to study the parasagittal compartmentalization of the cerebellum, which can be done using various molecular markers, the most well-known of which is Zebrin-II/Aldolase C (zebrin), a brain-specific glycolytic enzyme. Although the exact function of zebrin has yet to be elucidated, several studies have pointed to a neuroprotective role due to its expression pattern. In CS, a rare X-linked neurodevelopmental and neurodegenerative condition caused by loss of function mutations in the SLC9A6 gene, which encodes the endosomal Na+/H+ exchanger 6 (NHE6) protein, a prominent ataxic phenotype becomes evident early in life with debilitating consequences. The pathophysiology of CS is poorly understood, with no therapeutic treatments available. Using a mouse model recapitulating the patient phenotype of CS, we first set out to determine a timeline of zebrin-related PC vulnerability in CS. Here, we highlight a critical 10-day window of vulnerability between postnatal day (P)25-P35 in the CS cerebellum, with anterior lobe zebrin-negative PCs undergoing rapid and aggressive degeneration, while anterior zebrin-positive PCs showing high resilience until late stages of disease progression. Interestingly, we report a novel finding in the CS cerebellum that zebrin-related vulnerability is specific to the anterior lobe, with resilient posterior lobe PCs of different zebrin molecular identity being seemingly equally vulnerable in advanced disease stages. Elevated brain glutamate in the cerebellum is a hallmark finding in many ataxias, including CS patient brains. This elevation of cerebellar glutamate levels can lead to excitotoxic neuronal damage. Previously, we have shown that the loss of NHE6 leads to endosomal over acidification in the hippocampus, resulting in the mis-sorting of important proteins and receptors. Thus, we set out to investigate the elevated glutamate in the CS cerebellum in more detail, exploring pathophysiological alterations in the endocytic pathway of CS mice, with a focus on glutamate transporters. Here, we found that glial glutamate transporter EAAT1/GLAST, the most abundant glutamate transporter in the cerebellum, is downregulated following endosomal mis trafficking, with accumulation in lysosomes. Importantly, we show that Niclosamide, a modulator of endosomal acidification, can rescue cerebellar pathology and improve locomotor deficits in CS mice. Lastly, considering the similar pattern and progression of cerebellar degeneration in CS and ARSACS, we investigated whether alterations in levels of endosomal NHEs and cerebellar glutamate transporters could also be involved in the pathophysiology of ARSACS. We report downregulation in the levels of endosomal NHEs in the vulnerable anterior lobe of ARSACS mice, accompanied by changes in levels of cerebellar glutamate transporter levels, highlighting a potential mechanism of endocytic mis sorting in the ARSACS cerebellum. The findings of this thesis extend our understanding of the pathophysiology of cerebellar ataxia, providing a potential mechanism underlying the degeneration of PCs in CS and ARSACS, and propose a novel pharmacological treatment which could prove effective beyond the scope of CS ataxia

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