Neurodegeneration the RNA way

Abstract

The expression, processing, transport and activities of both coding and non-coding RNAs play critical roles in normal neuronal function and differentiation. Over the past decade, these same pathways have come under scrutiny as potential contributors to neurodegenerative disease. Here we focus broadly on the roles of RNA and RNA processing in neurodegeneration. We first discuss a set of "RNAopathies", where non-coding repeat expansions drive pathogenesis through a surprisingly diverse set of mechanisms. We next explore an emerging class of "RNA binding proteinopathies" where redistribution and aggregation of the RNA binding proteins TDP-43 or FUS contribute to a potentially broad range of neurodegenerative disorders. Lastly, we delve into the potential contributions of alterations in both short and long non-coding RNAs to neurodegenerative illness.

Fig. 1

Mechanisms underlying RNA mediated neurodegeneration in nucleotide repeat disorders. Bidirectional transcription atloci with expanded nucleotide repeats leads to the generation of multiple potentially toxic products. (A) Sense transcripts of tri-nucleotide CUG (shown here), CAG, or CGG repeats form secondary mRNA hairpin structures that can bind to and sequester RNA-binding proteins. (B and C) The decreased availability of RNA binding proteins such as splicing factors leads to alterations in the splicing and expression of other mRNAs in trans. Transcription factors and other nucleotide associated proteins may also be sequestered with effects on neuronal homeostasis. (D) Antisense transcription through the repeats leads to the generation of other potentially toxic mRNA sequences. These antisense transcripts sometimes contain open reading frames through the repeat, leading to translation of potentially toxic amino acid homopolymer production (e.g. polyglutamine containing proteins). (E) Homopolymer containing proteins may also be generated through a novel process known as repeat-associated non-ATG initiated (RAN) translation. Shown is the production of a polyglutamine peptide; however, alternative homopolymers in all three potential reading frames may be generated from each transcript.

Fig. 2

TDP-43 alterations in ALS and other neurodegenerative disorders. (A) TDP-43 is a nuclear protein which associates with the RNA polymerase Pol II on target DNA sequences, and participates in mRNA splicing. (B) Some TDP-43 is also exported from the nucleus associated with RNA-binding proteins on a subset of mRNAs. (C) Chronic neuronal stressors or mutations in TDP-43 lead to the translocation of the majority of TDP-43 to the cytoplasm. (D) This results in a loss of TDP-43s normal nuclear functions related to splicing and transcriptional regulation. (E) The increase in cytoplasmic TDP-43 results in a toxic gain-of-function via generation of TDP-43 protein aggregates as well as the accumulation of TDP-43 in cytoplasmic stress granules.