Alterations in the Na/H Exchanger NHE6 and Glutamate Transporters may Influence Purkinje Cell Fate in ARSACS.

Patterned cell death is a common feature of many neurodegenerative diseases. This is apparent in cerebellar Purkinje cells (PCs) in patients and mouse models of Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). In ARSACS, PCs in the anterior cerebellar vermis are vulnerable to degeneration while those in the posterior vermis are resilient. As the mechanisms underpinning cerebellar pathophysiology in ARSACS are not fully understood, we chose to investigate two important regulatory pathways for cellular health in neurons: (1) the autophagy-lysosome pathway which is important for the trafficking of cargo essential for proper neuronal function, as well as (2) excitatory amino acid transporters (EAATs) that regulate extracellular glutamate levels. Using a mouse model of ARSACS (Sacs/), we found a significant decrease in the Na/H exchanger 6 (NHE6) in the PCs in the vulnerable anterior but not resilient posterior cerebellum. We looked at two EAATs that are highly expressed in the cerebellum: EAAT1 and EAAT4. Glial EAAT1 levels were significantly reduced in both anterior and posterior lobules, which could lead to excitotoxicity. However, the neuronal EAAT4 protein was elevated only in the resilient posterior PCs, likely counteracting the effects of reduced EAAT1 in posterior cerebellum. These results point to possible impairment in the endocytic pathway in the ARSACS cerebellum, and an elevation of EAAT4 glutamate transporters in the resilient posterior lobules of the cerebellar vermis that may contribute to neuroprotection.