Altered RNA metabolism is a key pathophysiological component causing several neurodegenerative diseases. Genetic mutations causing neurodegeneration occur in coding and non-coding regions of seemingly unrelated genes whose products do not always contribute to the gene expression process. Several pathogenic mechanisms may co-exist within a single neuronal cell, including RNA/protein toxic gain-of-function and/or protein loss-of-function. Genetic mutations that cause neurodegenerative disorders disrupt healthy gene expression at diverse levels, from chromatin remodelling, transcription, splicing, through to axonal transport and repeat-associated non-ATG (RAN) translation. We address neurodegeneration in repeat expansion disorders (Huntington's disease, spinocerebellar ataxias, C9ORF72-related amyotrophic lateral sclerosis) and in diseases caused by deletions or point mutations (spinal muscular atrophy, most subtypes of familial amyotrophic lateral sclerosis). Some neurodegenerative disorders exhibit broad dysregulation of gene expression with the synthesis of hundreds to thousands of abnormal messenger RNA (mRNA) molecules. However, the number and identity of aberrant mRNAs that are translated into proteins - and how these lead to neurodegeneration - remain unknown. The RNA biology research field faces the challenge of identifying pathophysiological events of dysregulated gene expression. In conclusion, we discuss current research limitations and future directions to improve our characterisation of pathological mechanisms that trigger disease onset and progression.