Therapeutic potential of d-cysteine against in vitro and in vivo models of spinocerebellar ataxia

Exp Neurol. 2021 Sep;343:113791. doi: 10.1016/j.expneurol.2021.113791. Epub 2021 Jun 19.


Spinocerebellar ataxia (SCA) is a group of autosomal-dominantly inherited ataxia and is classified into SCA1-48 by the difference of causal genes. Several SCA-causing proteins commonly impair dendritic development in primary cultured Purkinje cells (PCs). We assume that primary cultured PCs expressing SCA-causing proteins are available as in vitro SCA models and that chemicals that improve the impaired dendritic development would be effective for various SCAs. We have recently revealed that D-cysteine enhances the dendritic growth of primary cultured PCs via hydrogen sulfide production. In the present study, we first investigated whether D-cysteine is effective for in vitro SCA models. We expressed SCA1-, SCA3-, and SCA21-causing mutant proteins to primary cultured PCs using adeno-associated viral serotype 9 (AAV9) vectors. D-Cysteine (0.2 mM) significantly ameliorated the impaired dendritic development commonly observed in primary cultured PCs expressing these three SCA-causing proteins. Next, we investigated the therapeutic effect of long-term treatment with D-cysteine on an in vivo SCA model. SCA1 model mice were established by the cerebellar injection of AAV9 vectors, which express SCA1-causing mutant ataxin-1, to ICR mice. Long-term treatment with D-cysteine (100 mg/kg/day) significantly inhibited the progression of motor dysfunction in SCA1 model mice. Immunostaining experiments revealed that D-cysteine prevented the reduction of mGluR1 and glial activation at the early stage after the onset of motor dysfunction in SCA1 model mice. These findings strongly suggest that D-cysteine has therapeutic potential against in vitro and in vivo SCA models and may be a novel therapeutic agent for various SCAs.

Keywords: D-cysteine; Dendritic development; Gliosis; Purkinje cells; Spinocerebellar ataxia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxin-1 / biosynthesis*
  • Ataxin-1 / genetics
  • Cells, Cultured
  • Cerebellum / drug effects*
  • Cerebellum / metabolism*
  • Cysteine / pharmacology
  • Cysteine / therapeutic use*
  • Female
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Pregnancy
  • Rats
  • Rats, Wistar
  • Spinocerebellar Ataxias / drug therapy*
  • Spinocerebellar Ataxias / genetics
  • Spinocerebellar Ataxias / metabolism*


  • Ataxin-1
  • Atxn1 protein, mouse
  • Cysteine