Several neurodegenerative diseases have a genetic basis, but the precise way in which the mutant genotype is translated into the pathological phenotype remains unclear. One possibility is that the mutant protein becomes toxic for the cell, leading to its demise. This concept has guided research aimed at establishing whether endogenous proteins can protect neurons from degeneration, pointing to new molecular targets for therapeutic intervention. Two recent studies illustrate the potential of this idea.

Some forms of Parkinson's disease (PD) have been linked to mutations in α-synuclein, and it has been proposed that the mutant protein alters the function of the ubiquitin–proteasome system. Petrucelli et al. tested this proposal and found that overexpressing mutant α-synuclein increased the sensitivity of cultured cells to proteasome inhibitors, at least in part by directly reducing proteasomal activity. Catecholaminergic neurons were particularly vulnerable, a finding that is consistent with the marked susceptibility of dopaminergic neurons in PD. Crucially, the overexpression of parkin, a ubiquitin ligase that has also been linked to PD, had a protective effect that depended on its ligase activity.

In the case of Huntington's disease, the production of the protein huntingtin with an expanded polyglutamine tract leads to cell degeneration. By expressing polyglutamine-containing fragments of huntingtin in Caenorhabditis elegans neurons, Faber et al. screened for genes that suppressed cell degeneration and identified polyQ enhancer-1 (pqe-1). Loss of pqe-1 function exacerbated neurodegeneration, whereas its overexpression had a protective effect. The PQE-1 protein has a domain rich in glutamine and proline residues that seems to be important for its protective action. Although no clear homologue of PQE-1 has been found in humans, it will be tempting to explore whether proteins with an equivalent domain can exert a similar protection.