The results of the ARSACS research project have been presented at the American Society for Cell Biology annual meeting held on Dec 6 in Denver, Colorado and have been posted on the following scientific websites:
The SACS is very large 9 exons gene that codes for one of the largest 4579 amino acids 521 kDa human protein that is relatively ubiquitously expressed but at much higher level in the central nervous system.
Sacsin is a multimodular protein, with the following 7 presently defined domains from N- to C-terminal: a ubiquitin-like domain that binds to the proteosome; three large sacsin repeat regions that may have an Hsp90-like chaperone function; an XPCB domain that binds to the Ube3A ubiquitin protein ligase; a DnaJ domain that binds Hsc70; and a higher eukaryotes and prokaryotes nucleotide-binding (HEPN) domain that mediates sacsin dimerization.
Sacsin was shown to colocalize with mitochondrial in neurons in culture and in the brain of rodents.
Knock down (KD) and Knock out (KO) of sacsin lead to abnormal mitochondrial fission and ensuing abnormal mitochondrial network, axonal and even greater dendritic neuronal morphological changes, and neuronal death in culture and in a transgenic KO mice model.
The KO mice develop age-dependant cerebellar neuronal Purkinje cell death and a progressive spastic and ataxic phenotype.