Misfolded proteins disrupt cellular functions in ALS and other diseases, but the precise mechanisms by which the cell recognizes and targets them for disposal are not well understood. In a new study published online May 29 in Molecular Cell, researchers led by Xiaolu Wang from University of Pennsylvania have identified a molecular tag team that removes misfolded proteins and protects from neurotoxicity. PML/TRIM19 recognizes aberrant properties of misfolded proteins, such as exposed hydrophoblic residues, and marks them for degradation with small ubiquitin-like modifiers (SUMOs). These tagged proteins are then marked by RNF4 with ubiquitin residues and then degraded by the proteasome machinery. The researchers demonstrate that deficiency in this pathway exacerbates neurodegenerative processes in a mouse model of spinocerebellar ataxia 1 (SCA1). Interestingly, this molecular pathway targets most types of misfolded proteins and protects the cells against their toxicity. Could defects in this machinery play a role in ALS? Click here to read more.
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