Various reported substrates of parkin include CDC-rel-1, O-glycosylated a-synuclein, the parkin-associated endothelin-like receptor, the [alpha]-synuclein--binding protein synphilin-1, actin filaments, the poly(Q)expanded mutant of ataxin-3
, Huntington disease polyglutamine proteins, the amyloidogenic Alzheimer disease A[beta] 1-42 peptide (amyloid-[beta] peptide 1-42), and a[beta]-tubulin.
Zalachoras et al., "Ataxin-3
protein modification as a treatment strategy for spinocerebellar ataxia type 3: removal of the CAG containing exon," Neurobiology of Disease, vol.
Onofre et al., "Silencing mutant ataxin-3
rescues motor deficits and neuropathology in Machado-Joseph disease transgenic mice," PLoS One, vol.
In these mice, the orexin promoter drives expression of the neurodegenerative gene ataxin-3
and leading to progressive loss of the orexin neurons during development.
Similarly, the expansion of glutamine residues in ataxin-3
leads to Machado-Joseph disease, which is a neurodegenerative disorder that occurs due to the accumulation of this toxic protein in the nucleus and the mitochondria.
These animals have been engineered to express the disease-associated proteins huntingtin and ataxin-3
. We have demonstrated both the versatility of C.
For instance, in the field of polyglutamine diseases, the Paulson group revealed that proteins in aggregates are shuttling inside and outside of aggregates by using fluorescence recovery after photobleaching (FRAP) and fluorescence loss in photobleaching (FLIP) on aggregates formed by green fluorescent protein-tagged polyglutamine disease proteins.38) Fluorescent fusion proteins of Ataxin-3
(disease protein of spinocerebellar ataxia type-3) and huntingtin (disease protein of Huntington's disease) recover after photobleaching was very slow, while FLIP did not show protein release from aggregates.
SCA3 ataxia (the most common one) results from a CAG-trinucleotide expansion in the coding region of the ATXN3 gene, leading to an expanded polyglutamine (polyQ) sequence within the Ataxin-3
Mez et al., "A mutant ataxin-3
putative-cleavage fragment in brains of Machado-Joseph disease patients and transgenic mice is cytotoxic above a critical concentration," Journal of Neuroscience, vol.
It is caused by CAG triplet repeat expansions that encode an expanded polyglutamine (polyQ) tract in the disease-related protein, ataxin-3
The data featured at the conference demonstrated mechanistic proof-of-concept of the non-allele-specific ataxin-3
protein-silencing approach by using artificial microRNA candidates engineered to target the ataxin-3
gene in a SCA3 knock-in mouse model.