New old drug(s) for spinocerebellar ataxias

Ady, Visou; Watt, Alanna J.

doi:10.1113/jp273149

Cited by 1 publication

(1 citation statement)

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“…It is possible that treatments targeted at firing and synaptic deficits may thus be a general means of treating diverse ataxias (Meera et al . ; Ady & Watt, ), a worthwhile goal since ataxias are rare diseases. Nonetheless, we observe several findings that must lead to caution.…”

Section: Discussionmentioning

confidence: 99%

Altered synaptic and firing properties of cerebellar Purkinje cells in a mouse model of ARSACS

Ady

Toscano-Márquez

Nath

et al. 2018

The Journal of Physiology

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Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that includes a pronounced and progressive cerebellar dysfunction. ARSACS is caused by an autosomal recessive loss-of-function mutation in the Sacs gene that encodes the protein sacsin. To better understand the cerebellar pathophysiology in ARSACS, we studied synaptic and firing properties of Purkinje cells from a mouse model of ARSACS, Sacs mice. We found that excitatory synaptic drive was reduced onto Sacs Purkinje cells, and that Purkinje cell firing rate, but not regularity, was reduced at postnatal day (P)40, an age when ataxia symptoms were first reported. Firing rate deficits were limited to anterior lobules that later display Purkinje cell death, and were not observed in posterior lobules where Purkinje cells are not lost. Mild firing deficits were observed as early as P20, prior to the manifestation of motor deficits, suggesting that a critical level of cerebellar dysfunction is required for motor coordination to emerge. Finally, we observed a reduction in Purkinje cell innervation onto target neurons in the deep cerebellar nuclei (DCN) in Sacs mice. Together, these findings suggest that multiple alterations in the cerebellar circuit including Purkinje cell input and output contribute to cerebellar-related disease onset in ARSACS.

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Section: Discussionmentioning

confidence: 99%