[Abstract Title]. - Society for Neuroscience

Disclosures: G. Sciamanna, None; A. Tassone, None; P. Bonsi , None; A. Tscherter, None; N.
Sharma, None; D.G. Standaert, None; A. Pisani, None; G. Martella, None.
Poster
248. Dystonia
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 248.9/U8
Topic: C.03.j. Dystonia
Support: NIH/NINDS (K02 NS058450)
Title: Differences in torsinA degradation caused by the disease-linked mutation reveal potential
therapeutic approaches for DYT1 dystonia
Authors: *K. L. GORDON 1 , P. GONZALEZ-ALEGRE 2 ;
1 Program in Neurosci, 2 Grad. Programs in Neurosci, Genetics, and Mol & Cell Bio, and Dept of
Neurol., Univ. Iowa, Iowa City, IA
Abstract: DYT1 dystonia is a disabling neurological disease caused by a glutamic acid deletion
in torsinA (torsinA(ΓE)). The mutation causes torsinA(ΓE) to redistribute from the endoplasmic
reticulum (ER) to the nuclear envelope (NE) and to form abnormal intermolecular disulfide-link
dependent oligomers. Although how neurons handle disease-linked proteins has been addressed
in many disorders, how cells dispose of torsinA remains unexplored. As an ER protein, torsinA
is a potential substrate for degradation through macroautophagy or the ubiquitin proteasome
system. Here, we aimed to identify the preferential catabolic pathway for torsinA and to
determine if the change in localization and oligomerization of torsinA(ΓE) modulates this
process.
Initial experiments in overexpression systems showed that both forms of torsinA can be cleared
by the proteasome and macroautophagy, but suggested that high levels of overexpression likely
saturate their normal degradation route and recruit alternative pathways. We optimized a cellular
system with expression at near physiological levels and determined that wild type torsinA is
preferentially degraded by macroautophagy. This was confirmed for endogenous torsinA in SH-
SY5Y cells. In contrast, torsinA(ΓE) is equally cleared by the proteasome and macroautophagy.
In subsequent studies, we determined that torsinA(ΓE) oligomerization is not a result of NE
localization but is linked to abnormal torsinA function, suggesting this molecular event might be
important in DYT1 pathogenesis. Interestingly, torsinA(ΓE) oligomers were cleared by
macroautophagy, and not the proteasomal system as is the monomeric form.
These studies suggest the turnover of torsinA is normally mediated by macroautophagy, but the
disease-linked mutation targets torsinA to the proteasome. However, the presence of abnormal