gr
grandrounds
young individuals and that sets up differ-
ent regions for decline later in life."
A M o S t U n e x p e c t e d o U tco M e
the finding emerged unexpectedly
from McConnell's investigations into
schizophrenia. it was in that context that
he and his collaborators first discovered
the unexpected variation in the genetic
makeup of individual brain cells. that
discovery may help explain not just
schizophrenia but depression, bipolar
disorder, autism and other conditions.
Continuing his investigations,
McConnell expected that this mosaicism
would increase with age—that mutations
would accumulate over time. What he and
his collaborators at Johns Hopkins found is
exactly the opposite: Younger people had
the most mosaicism and older people had
the least.
"We wound up building an atlas that
contained neurons from 15 individuals.
None of these individuals had disease,"
On the Case
of a Deadly
Mystery
Discovery may provide clues
into cell death seen
in Alzheimer's, Parkinson's
UVA researcher Michael
McConnell, PhD
S
cientists at the University
of Virginia school of
Medicine have identified
a potential explanation for the
mysterious death of specific
brain cells seen in alzheimer's,
Parkinson's and other neurode-
generative diseases.
the new research suggests
that the cells may die because
of naturally-occurring gene
variation in brain cells that
until recently were assumed
to be genetically identical.
this variation—called "somatic
mosaicism"—could explain
why neurons in the temporal
lobe are the first to die in
alzheimer's, for example, and
why dopaminergic neurons are
the first to die in Parkinson's.
"this has been a big open
question in neuroscience,
particularly in various neuro-
degenerative diseases," said
neuroscientist Michael McCon-
nell, PhD, of UVa's Center for
Brain immunology and Glia
(BiG). "What is this selective
vulnerability? What underlies
it? and so now, with our
work, the hypotheses moving
forward are that it could be
that different regions of the
brain actually have a different
garden of these variations in
"What's really interesting about mosaicism
is that it is fundamentally tweaking
our assumptions about what nature is,
because we've kind of always assumed
that every cell in any given individual had
the same genome, the same DNA in every
cell." —Michael McConnell, PhD
2 Vitals Spring 2019
