Aggregation party in ALS

Abstract

Aggregation and mislocalization of TDP-43 are at the heart of amyotrophic lateral sclerosis, but it is difficult to manipulate the protein directly because of its broad role in cellular survival. University of Pennsylvania researchers now have found evidence that TDP-43 interacts with ataxin 2, an intracellular protein linked to another neurodegenerative disease, spinocerebellar ataxia, and think that inhibiting ataxin 2 activity could provide a handle for preventing the toxicity caused by mislocalized Mutations in TAR DNA binding protein 43 (TDP-43; TARDBP) lead to certain rare cases of hereditary amyotrophic lateral sclerosis (ALS), and in a majority of ALS patients the normally soluble protein mislocalizes into aggregates. 2But tinkering with TDP-43 levels can disrupt neurological development, complicating efforts to study the protein's function in mice.A team led by Aaron Gitler, assistant professor of cell and developmental biology at the University of Pennsylvania, chose a simpler approach to understanding TDP-43's role in the cell. Instead of mouse studies, the group screened for genes that affected TDP-43's aggregation and toxicity in yeast, then extended the findings through a series of more complex models of TDP-43 pathology ranging from flies to cell culture to ALS patients.The yeast work was done with a screening platform Gitler helped develop while he was a postdoc in the laboratory of Susan Lindquist, a professor of biology at the Massachusetts Institute of Technology and the Whitehead Institute for Biomedical Research. Lindquist is a cofounder of FoldRx Pharmaceuticals Inc., a company that develops drugs to treat diseases caused by protein misfolding. The screening platform is licensed to FoldRx.FoldRx is being acquired by Pfizer Inc. "We've provided evidence for a potentially novel risk factor for ALS," said Gitler. "This underscores the power of simple model systems like yeast and flies in identifying modifiers of disease." "This is a validation of yeast as a model system and of TDP-43 as a target," said FoldRx CEO Richard Labaudinière. Call to ATXN2Gitler's team previously reported that overexpression of TDP-43 kills yeast cells. 3 In a new report published in Nature, his group identified 13 yeast genes whose overexpression increased toxicity caused by TDP-43 compared with that seen in vector-treated controls. Among these was pbp1, which encodes an mRNA-associated protein that strongly resembles human ataxin 2 (ATXN2; SCA2). The team also found that pbp1 deletion decreased TDP-43 toxicity compared with wild-type pbp1 expression.Gitler's team then collaborated with UPenn biology professor Nancy Bonini to test whether tinkering with ATXN2 gene levels increased or decreased TDP-43 toxicity in a fly model of neurodegeneration. Overexpression of an ALS-linked allele of TDP-43 in fly eyes and motor neurons led to cell degeneration and loss of motility compared with those in wild-type controls.Just as in yeast, increasing levels of the fly homolog of ATXN2 exacerbated TDP-43's toxicity, whereas halvi...