Hexanucleotide repeat expansions in C9orf72 gene locus create double jeopardy, first by leading to DNA–RNA R-loops that spawn double-strand breaks and second by the synthesis of dipeptide repeats that hinder DNA repair. This two-pronged mechanism may explain neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia.

Neurons require lifelong maintenance of their transcriptional program, which includes stable expression of cell-type-specific identity genes. A study now shows that PRC2-mediated chromatin repression in adulthood is critical for the maintenance of neuronal identity gene expression and neuronal survival.

Does cell-to-cell spreading of misfolded proteins occur in all neurodegenerative disorders? A study in this issue of Nature Neuroscience now demonstrates propagation of mutant huntingtin in brain slice cultures and in vivo, thereby extending the process of cell-to-cell propagation of misfolded proteins to Huntington's disease.