Cell machinery may take on new roles tied to SMA, study suggests

Proteins involved in producing histones, which help package DNA inside cells, may take on new roles in mature nerve and muscle cells, a U.S.-Polish study found. The findings could provide new clues about spinal muscular atrophy (SMA).

Researchers found that as nerve and muscle cells matured and stopped dividing, several components of this histone-producing machinery were found in the surrounding cytoplasm rather than concentrated in the nucleus. The unexpected shift suggests they may be repurposed for other functions in mature cells.

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What those functions are remains unknown, but the researchers uncovered clues suggesting the proteins could be involved in communication between motor neurons, the nerve cells that control movement, and muscle fibers.

The findings may be particularly relevant to SMA because assembly of part of this machinery depends on the survival motor neuron (SMN) protein, which is deficient in people with the disease. The researchers said the findings could therefore provide new insight into the biological processes underlying SMA.

The study, “Are components of the histone gene expression machinery functionally repurposed in terminally differentiated cells?,” was published in Biology Open.

When a cell prepares to divide, it must first copy its DNA. At the same time, it rapidly produces histones, proteins that package the newly copied DNA into chromatin, the complex of DNA and proteins that make up chromosomes. Histone production and DNA replication must therefore be tightly coordinated.

One protein involved in this process, NPAT, switches on histone genes. This produces RNA instructions that must then be properly processed before they can be used to make histones. That job is carried out by a molecular complex called U7 small nuclear ribonucleoprotein (U7 snRNP).

The core of U7 snRNP contains RNA surrounded by a ring of proteins, including one called Lsm11. Another protein, FLASH, binds Lsm11 and helps U7 snRNP process the RNA instructions used to make histones.

In dividing cells, this machinery gathers around histone genes in structures inside the nucleus called histone locus bodies (HLBs), helping coordinate histone production with DNA replication.

But that raises an interesting question. Mature skeletal muscle cells and neurons have permanently stopped dividing. They no longer need the massive, recurring supply of histones required to pack newly copied DNA during cell division. What, then, happens to the machinery previously dedicated to making histones?

Researchers track protein shifts as nerve and muscle cells mature

To investigate, a team of researchers in the U.S. and Poland studied two human cell models. They induced skeletal muscle precursor cells, called myoblasts, to develop into nondividing myotubes, a more mature form of muscle cell. They also induced human embryonic stem cells to develop into nondividing cortical neurons, a type of nerve cell in the brain.

Before the cells matured, NPAT and FLASH were concentrated in HLBs inside the nucleus, while Lsm11 — as part of the U7 snRNP core — was more broadly distributed throughout the nucleus. As the muscle and nerve cells matured and stopped dividing, the HLBs disappeared, and NPAT, FLASH, and Lsm11 were found in the cytoplasm. In the neurons, the proteins were also observed moving out of the nucleus toward the cytoplasm.

Together, the results raise the possibility that these components don’t simply become obsolete when nerve and muscle cells stop dividing. Instead, the researchers proposed, they may be repurposed for other functions in mature cells. What those functions are remains unknown.

The team did, however, find a possible clue.

In experiments looking for proteins that interact with Lsm11 and FLASH, the researchers identified a protein called Snapin that interacted with both. Snapin has previously been implicated in several processes, including the release and recycling of synaptic vesicles — tiny packages used by nerve cells to release chemical signals and communicate with each other.

The researchers cautioned that the interactions with Snapin need further confirmation. But they said the finding raises the possibility that Lsm11 and FLASH could play roles in processes near the cell membrane, potentially including the release of synaptic vesicles.

Findings may offer new clues to SMA biology

This potential new role takes on particular interest in SMA because Lsm11 is part of the ring of proteins that form the U7 snRNP core, whose assembly depends on the SMN protein. Despite decades of research, however, it remains unclear whether SMA results from problems assembling these protein rings or from another, tissue-specific function of SMN.

Previous work cited by the researchers has shown that SMN can regulate assembly of the SNARE complex, which is involved in releasing chemical signals at neuromuscular junctions — the specialized connections where motor neurons communicate with muscle fibers.

Putting these observations together, the researchers proposed that once muscle and nerve cells stop dividing, components of the histone-producing machinery — including FLASH and components of U7 snRNP such as Lsm11 — may act together with Snapin and SMN to facilitate communication between motor neurons and muscle fibers, “hence maintaining the integrity and functionality of [neuromuscular junctions],” the researchers wrote.

“While hypothetical, this reasoning suggests future research avenues in studying SMA, potentially providing new insights into the pathophysiology of this neuromuscular syndrome,” the researchers concluded.