Study detects origins of Huntington's disease in two-week-old human
embryos

Date:
October 5, 2021
Source:
Rockefeller University
Summary:
The findings shed new light on the root causes of this disease,
which leads to the degeneration of neurons in midlife.



FULL STORY ========================================================================== Huntington's disease is a fatal condition involving the death of brain
cells, typically striking in midlife. But new findings suggest the disease process starts decades earlier. Although symptoms emerge in adulthood, researchers have been able to detect the earliest effects of Huntington's
in the first two weeks of human embryonic development. 

==========================================================================
The findings recast Huntington's, often considered a neurodegenerative condition, as a developmental disease, and point to new approaches for
finding treatments for a disease that currently has no cure or therapies.

"When the patient goes to the doctor, that's when the last dominoes have fallen. But the first domino is pushed in the developmental phase,"
says Ali Brivanlou, head of the Laboratory of Synthetic Embryology
at Rockefeller University, who published the findings in the journal Development. "Knowing this trajectory, we may be able to block the
progression of the disease." Early beginnings Huntington's is caused
by mutations in a single gene, Huntingtin, resulting in the production
of an unusually long protein. The gene is expressed in the fertilized
egg and subsequently in every cell of the body, but its functions are
not entirely known. A bigger mystery is why the defective gene appears
to be detrimental only to neurons in specific parts of the brain.

Previously researchers in the Brivanlou lab found evidence that
abnormalities due to Huntingtin mutation arise decades before the neurons
start to perish: In the first stages of the brain development in the
embryo, when uniform cells are becoming specific brain cell types and
forming structures. Introducing the Huntington's mutation in these
developing cells led to abnormal neurons and structures.



========================================================================== Huntington's signature In the new study, researchers examined the effects
of Huntington's mutation at an earlier stage, called gastrulation, during
which the two-week-old embryo starts to form the three embryonic germ
layers, from which the progenitors of all cell types, including brain
cells emerge.

For the study, the researchers created synthetic human embryos --
lab-generated embryos that are derived from stem cells and mimic the
behavior of human cells during the early stages of development. They
then used the gene-editing method CRISPR/Cas9 to insert the range of Huntington's mutations found in people with the disease into the embryos.

Comparing the embryos with and without the mutation revealed a pattern:
the mutations affected the size of germ layers. And the more severe
mutations led to larger differences. "It's a phenotypic signature --
you can see it with your eyes," says Brivanlou, the Robert and Harriet Heilbrunn Professor.

That visible change, the researchers found, is caused by alteration
to a signaling pathway that guides the embryonic cells.  New
approaches to cures How exactly such early changes affect the development
of embryos later on is unclear. But people with these mutations are born
and function normally for years. Researchers suspect that a developing
embryo uses certain mechanisms to compensate for the deleterious effects
of Huntington's mutations.

"Understanding those mechanisms may be the key to developing new
treatments that delay the symptoms, or even cure the disease," Brivanlou
says.

Using synthetic human embryos as their platform, the researchers have
started to screen for drugs that can correct these abnormalities. This approach, they hope, will lead to developing clinical interventions
that will address the causes of Huntington's disease, and not just the consequences.

========================================================================== Story Source: Materials provided by Rockefeller_University. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Szilvia Galgoczi, Albert Ruzo, Christian Markopoulos, Anna Yoney,
Tien
Phan-Everson, Shu Li, Tomomi Haremaki, Jakob J. Metzger, Fred Etoc,
Ali H. Brivanlou. Huntingtin CAG expansion impairs germ layer
patterning in synthetic human 2D gastruloids through polarity
defects. Development, 2021; 148 (19) DOI: 10.1242/dev.199513 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211005124719.htm

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