Brain: A novel mechanism for the mislocalization of RNA-binding proteins in amyotrophic lateral sclerosis

Guide:

Past studies have shown that introns retain (IR) more frequently in mammals than were initially identified, affecting transcripts of most genes
.

IR has previously been involved in regulating the transcriptome
by coupling to the RNA degradation pathway.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing and incurable disease that causes relatively selective degeneration of motor neurons (MNs
).

Recent studies have described IR as a major splicing event, which characterizes the early stages of motor neuron lineage restriction from human iPSCs, interfered with
by genetically diverse ALS mutagenicity.

On March 9, 2021, the Rickie Patani team at the University of London published an article
on Brain as: "Aberrant cytoplasmic intron retention is a blueprint for RNA binding protein mislocalization in amyotrophic lateral sclerosis".

The study used time-resolved hiPSCs for deep sequencing of the nuclear and cytoplasmic parts of motor neurogenesis, revealing that mutations in the VCP gene causing ALS lead to the accumulation of compartmental-specific abnormalities in IRT
.

1.

Time-resolved cell isolation and RNA sequencing during human motor neurogenesis reveal a wide range of abnormal cytoplasmic IRs in ALS
.

Figure 1: Time-resolved cell fractionation and RNA sequencing during human motor neurogenesis reveal a wide range of abnormal cytoplasmic IRs in ALS

2.

The study found that a large number of IRTs (including SFPQ, OGT, TUSC3, and DDX39) exhibit a specific increase in cytoplasmic abundance in VCPmu cultures, suggesting that VCP mutations lead to abnormal nuclear output and/or cytosolic stabilization of specific classes of IRTs, thus leading to cellular dysfunction
.

Figure 2: Abnormal nuclear and cytoplasmic intron sequences exhibit distinct features

3.

Previous studies have shown that reserved introns are, on average, shorter and G/C rich, and this study found that only introns that are primarily retained by nuclear abnormalities exhibit these characteristics
.

The study further examined the nature of
the interaction between RBP and abnormal cytoplasmic IRT using a richer dataset.

This further suggests the disruption
of post-transcriptional splicing in the pathogenesis of ALS.

Figure 3: Cytoplasmic intron-reserved transcripts create an environment prone to mispositioning for bound rbp

Summary and outlook

In summary, this study shows that transcripts that exhibit most of the transient IR during neuronal development are only present in the nucleus, but are transiently localized in the cytoplasm, and this transcript pool has a strong binding affinity
for RBP.

In summary, this study suggests that cytoplasm-reserved introns act as RNA regulators in the steady-state control of RBP localization, and that an abnormal increase in cytoplasmic IR transcripts associated with ALS disrupts this process
.