Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS [MIM 270550]) is an early-onset neurodegenerative disorder caused by mutations in the SACS gene. Over 200 SACS mutations have been identified. Most mutations lead to a complete loss of a sacsin, a large 520 kD protein, although some missense mutations are associated with low levels of sacsin expression. We previously showed that Sacs knock-out mice demonstrate early-onset ataxic phenotype with neurofilament bundling in many neuronal populations. To determine if the preservation of some mutated sacsin protein resulted in the same cellular and behavioral alterations, we generated mice expressing an R272C missense mutation, a homozygote mutation found in some affected patients. Though SacsR272C mice express 21% of wild type brain sacsin and sacsin is found in many neurons, they display similar abnormalities to Sacs knock-out mice, including the development of an ataxic phenotype, reduced Purkinje cell firing rates, and somatodendritic neurofilament bundles in Purkinje cells and other neurons. Together our results support that Sacs missense mutation largely lead to loss of sacsin function.Electronic supplementary materialThe online version of this article (10.1186/s13041-019-0438-3) contains supplementary material, which is available to authorized users.

SummarySensory neurons continually adapt their processing properties in response to changes in the sensory environment or the brainʼs internal state. Neuromodulators are thought to mediate such adaptation through a variety of receptors and their action has been implicated in processes such as attention, learning and memory, aggression, reproductive behaviour and state-dependent mechanisms. Here, we review recent work on neuromodulation of electrosensory processing by acetylcholine and serotonin in the weakly electric fish Apteronotus leptorhynchus. Specifically, our review focuses on how experimental application of these neuromodulators alters excitability and responses to sensory input of pyramidal cells within the hindbrain electrosensory lateral line lobe. We then discuss current hypotheses on the functional roles of these two neuromodulatory pathways in regulating electrosensory processing at the organismal level and the need for identifying the natural behavioural conditions that activate these pathways.

Patterned cell death is a common feature of many neurodegenerative diseases. In patients with autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and mouse models of ARSACS, it has been observed that Purkinje cells in anterior cerebellar vermis are vulnerable to degeneration while those in posterior vermis are resilient. Purkinje cells are known to express certain molecules in a highly stereotyped, patterned manner across the cerebellum. One patterned molecule is zebrin, which is expressed in distinctive stripes across the cerebellar cortex. The different zones delineated by the expression pattern of zebrin and other patterned molecules have been implicated in the patterning of Purkinje cell death, raising the question of whether they contribute to cell death in ARSACS. We found that zebrin patterning appears normal prior to disease onset in Sacs–/– mice, suggesting that zebrin-positive and -negative Purkinje cell zones develop normally. We next observed that zebrin-negative Purkinje cells in anterior lobule III were preferentially susceptible to cell death, while anterior zebrin-positive cells and posterior zebrin-negative and -positive cells remained resilient even at late disease stages. The patterning of Purkinje cell innervation to the target neurons in the cerebellar nuclei (CN) showed a similar pattern of loss: neurons in the anterior CN, where inputs are predominantly zebrin-negative, displayed a loss of Purkinje cell innervation. In contrast, neurons in the posterior CN, which is innervated by both zebrin-negative and -positive puncta, had normal innervation. These results suggest that the location and the molecular identity of Purkinje cells determine their susceptibility to cell death in ARSACS.

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