Research on Molecular Changes in PWS Sheds New Light on High Autism Risk

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by Marta Figueiredo PhD |

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The activity of nine genes located outside the so-called PWS locus — a region containing genes in Prader-Willi syndrome (PWS) that are lost or have defects — is significantly altered in people with the disease, according to a study in lab-grown nerve cells derived from patients and healthy individuals.

Researchers say this set of genes may represent a new molecular signature for PWS, given previous evidence that supports a link between most of these genes and neurodevelopmental processes — and that these activity changes were present regardless of the genetic cause of the specific PWS type.

In addition, molecular abnormalities in mitochondria, which are the powerhouses of cells, were detected in nerve cells from certain PWS patients with possible autism spectrum disorder (ASD). That suggests a link between such defects in these patients and a high risk of developing autism, the scientists said.

Overall, these findings provide greater insight on the molecular mechanisms of PWS and its associated higher risk of autism and may help to identify new therapeutic targets and approaches, the researchers noted.

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The study, “Molecular Changes in Prader-Willi Syndrome Neurons Reveals Clues About Increased Autism Susceptibility,” was published in the journal Frontiers in Molecular Neuroscience.

PWS is caused by the loss of function of genes located on the paternally inherited chromosome 15 that control appetite, metabolism, growth, intellectual function, and social behavior.

The most common cause of the disease is a deletion of this region, which is known as the PWS locus. A smaller percentage of cases is caused by the inheritance of two copies of chromosome 15 from the mother rather than one from the mother and another from the father — a condition dubbed maternal uniparental disomy, or UPD.

Notably, UPD-associated PWS results in milder disease, but a higher risk of ASD in comparison with PWS caused by genetic deletion.

Now, a team of researchers at the University of Tennessee Health Science Center set out to identify the molecular cause for the increased autism risk among PWS-UPD patients. The researchers analyzed gene activity changes between lab-grown nerve cells derived from PWS patients and those of typically developing people.

The study was funded by a pilot research grant from the Foundation for Prader-Willi Research.

Nerve cells were generated from dental pulp stem cells collected from four patients with PWS locus deletion, called the PWS-del group, and eight PWS-UPD patients — four with possible ASD — dubbed the PWS-UPD+ASD group. Cells also were collected from four typically developing people, who served as the control group.

Results from the gene activity analysis first revealed a core PWS molecular signature comprised of three genes within the PWS locus, specifically SNRPN, SNURF, and MAGEL2, and nine genes located outside that region. All three PWS locus genes were suppressed, as expected.

Six of these additional genes — PEX10, CTDP1, DHRS1, AKT1S1, MYL5, and TMEM92 — were significantly suppressed across all subgroups of PWS patients relative to the control group. Meanwhile, three genes, namely SNTB2, ATP7A, and MIPOL1, were significantly activated.

Notably, all nine genes but TMEM92 had previous evidence linking them to neurological processes, neurodevelopmental abnormalities, or PWS-like symptoms, further emphasizing their potential role in the development of PWS features.

Moreover, a specific molecular signature — reflecting a global suppression of genes involved in mitochondrial compartments, functions, and pathways — distinguished the PWS-UPD+ASD group from all the other groups.

In agreement, the team found that nerve cells derived from PWS-UPD patients with possible ASD had fewer, mislocalized, and aggregated (clumped) mitochondria, compared with nerve cells from individuals in the other groups.

This suggests that “mitochondrial dysfunction may contribute to increased ASD risk in [PWS-UPD patients],” the researchers wrote, adding that mitochondrial deficits have been previously reported in another cell type of PWS patients, as well as mitochondrial differences between PWS-del and PWS-UPD patients.

Notably, given that nerve cell communication requires a large amount of energy, “it is not surprising that mitochondrial defects have been implicated in both neurodevelopmental and neurodegenerative disorders,” and that they may contribute to a higher risk of autism in PWS-UPD patients, the researchers wrote.

“These studies are the first steps at investigating the molecular defects in PWS neurons contributing to both PWS symptomology and increased autism incidence in PW-UPD cases,” the team added.

More studies are needed to better understand the function of the genes comprising PWS’ molecular signature, which in turn may lead to the discovery of potential therapeutic targets for future interventions, the scientists said.

The team now plans to evaluate the effects of rescuing mitochondrial functions in nerve cells derived from PWS-UPD patients with possible ASD using currently available mitochondrial-targeted compounds. This may lead to the identification of potential therapies for this subgroup of PWS patients.