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TPI deficiency and neurodegeneration in Drosophila: an AGE‐dependent link to a common mechanism?

We have conducted forward screens in Drosophila to identify genes required for maintenance of neuronal viability. wasted away (wstd), is defined by a hypomorphic, autosomal recessive mutation associated with progressive motor impairment, severely reduced lifespan, and vacuolar neuropathology. Molecular analysis demonstrates that wstd encodes the glycolytic enzyme, triosphosphate isomerase (TPI). Mutations causing TPI deficiency have also been identified in humans resulting in progressive neurological dysfunction, neurodegeneration and early death. However, the mechanistic basis of the human syndrome remains puzzling. Decreased ATP levels do not appear to cause the observed phenotypes in TPI deficient flies or humans because ATP levels remain normal. Moreover, we find no genetic evidence that the mutant TPI is misfolded or involved in aberrant protein‐protein associations. We propose instead that the enzymatic block in wstd mutants leads to an accumulation of methylglyoxal and the consequent enhanced production of advanced glycation endproducts (AGEs), which are ultimately responsible for death and dysfunction of TPI deficient neurons. Evidence in support of this interpretation will be described. Our results favor the idea that TPI serves an essential neuroprotective role and support the possibility that AGEs may also contribute to the pathogenesis of other human neurological disorders.