June 24, 2021


by: admin


Tags: Autismlinked, brain, cell, disrupt, migration, mutation, Spectrum


Categories: autism

Autism-linked mutation might disrupt mind cell migration | Spectrum

Disorganized scaffolds: Immature brain cells from mutant CUL3 mice have a disordered cytoskeleton (right) compared to controls (left).

Mutations in CUL3, a leading autism gene, can disrupt the movement of neurons during development and disrupt the precise assembly of the brain, suggests a new study.

Correcting this misdirection could lead to therapy for autism in people with CUL3 mutations, the researchers say.

Mutations that disable CUL3 are not only associated with autism, but also with varying degrees of intellectual disability, movement problems, attention deficit hyperactivity disorder, epilepsy, and sleep disorders. Scientists have thoroughly studied how the protein encoded by CUL3 helps tag and break down other expendable proteins in cells, but much is still unknown about its role in the developing brain.

For the new work, the researchers created mice that have only one functioning CUL3 gene instead of the usual two. These mice have movement problems, decreased sociability, and poor memory – traits that are reminiscent of people with CUL3 mutations.

The team also constructed mice in which they could turn off a copy of CUL3 by giving the rodents the cancer drug tamoxifen. Turning off CUL3 in 30-day-old juvenile mice had little effect, suggesting that CUL3 mutations contribute to autism-like behavior during brain development, the researchers say.

Identifying this window “is vital for future critical studies,” says lead researcher Gaia Novarino, Professor of Neuroscience at the Institute for Science and Technology in Klosterneuburg, Austria.

Skeleton Crew:

CUL3 activity in mouse embryonic brain reaches peak levels Novarino’s team found out that pregnancy was 14.5 to 16.5 days. The activity pattern corresponded to that of human brain development: it was highest in the cortex, the seat of higher mental functions, and in the hippocampus, an area of ​​the brain that is connected to memory, as well as in certain neurons that can either stimulate or dampen brain activity.

During this peak time, migrating neurons in the mutant CUL3 mice travel slower and shorter distances than normal, the researchers found. And cells in the cortex have abnormal stratification – for example, the top and bottom layers of cells are unusually thin. The results were published in Nature Communications in May.

The animals’ brains exhibit abnormal levels of protein that are involved not only in nervous system development and cell migration, but also in helping cells maintain their shape. Previous research suggested that autism-related mutations in CUL3 could alter brain structure by disrupting these “cytoskeletal” proteins.

One such protein, PLS3, in particular, is constantly increased in the mutated CUL3 mice, the scientists discovered. Experiments with immature brain cells grown in the laboratory showed that this protein plays an important and previously unrecognized role in the migration of neurons – the higher its concentration, the slower these cells move. The cells also have disordered cytoskeletons, which likely explains their migration problems.

“Disorders with manifestations as diverse as autism are particularly difficult to explain with a single gene,” says Asya Rolls, an adjunct professor of neuroscience and immunology at the Technion-Israel Institute of Technology in Haifa, who was not involved in the work. “This study clarifies many of the features of this disorder by identifying a new actor in neural migration.”

Using the CRISPR gene editing technique to increase CUL3 gene activity in CUL3 mutant mice, the researchers restored typical PLS3 levels and neuronal migration patterns. However, targeting CUL3 and PLS3 could prove difficult in humans, as all possible therapies based on this strategy would have to work early in human development, Novarino says.

Potential therapies aimed at reactivating genes must be further developed before they can be considered viable. Still, “the field of gene therapy is developing at a rapid pace, so the future could be bright,” says Karun Singh, an adjunct professor of medicine at the University of Toronto in Canada, who was not part of the research.


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