Nature: Cell management processes involve deadly neurological disorders

Huntington's disease is a fatal inherited neurodegenerative disease caused by genetic errors at birth, although its symptoms usually do not begin until middle age
.
Scientists at Washington University School of Medicine in St.
Louis have been trying to understand how the aging process triggers symptoms, hoping that this knowledge could inform treatments that delay or prevent neurodegeneration
.

To that end, a new study from the University of Washington suggests that as patients age, the disease gradually disrupts an important cellular housekeeping process, known as autophagy, which is responsible for removing waste from
cells.
This cleanup is important in Huntington's disease because the accumulation of waste products in one particular neuron can lead to premature death
of such cells.

The researchers also showed that enhancing the autophagy pathway of neurons produced from skin cells from Huntington's patients could protect these cells from death
.

Senior author Andrew S.
Yoo, Ph.
D.
, professor of developmental biology at the University of Washington, said: "Our study sheds light on how aging triggers the loss of autophagy, a key process, and hints at how we might try to restore this important function to delay or even prevent Huntington's disease
.
"

The study, published Oct.
27 in the journal Nature Neuroscience, may also provide clues
to understanding cognitive decline in the aging process.

Huntington's disease destroys a specific type of brain cell called a middle spinous neuron, the loss of which can lead to involuntary muscle movements, impaired mental health, and cognitive decline
.
Patients usually live about
20 years after the first symptoms appear.

In this study, the researchers used a technique they developed to reprogram patients' skin cells into medium-spiny neurons, which allows adult skin cells to directly transform into various types of brain cells, depending on the specific formulation
of the signaling molecules that the skin cells are exposed to.
More common techniques include the use of stem cells — but stem cells reset the cell's biological clock to an early developmental state, which is useless for studying diseases that only show symptoms in adulthood
.

"We collected skin cell samples from different patients of different ages and modeled the disease before and after the onset of symptoms, which allowed us to identify differences between
younger and older Huntington's disease patients," Yoo said.
"We know that as patients age, something is bound to change
.
They all have mutations in
the huntingtin gene.
We wanted to find out the difference
between young patients who had no symptoms and older patients who actively showed signs of disease.
”

Yoo and his colleagues, including co-first authors Dr.
younggmi Oh and Seongwon Lee, PhD, both staff in Yoo's lab, found that medium-spined neurons reprogrammed from the skin cells of elderly patients with symptomatic Huntington's disease produced very high levels of a microRNA molecule
called miR-29b-3p.
This high level
was not found in reprogrammed neurons in young Huntington's patients, or in healthy individuals of any age.
The researchers showed that microRNAs set off a cascade of events, including autophagy
that damages these cells.
When skin cells complete their transformation into neurons, they begin to produce problematic microRNAs, autophagy slows down, and cells begin to die
.

The researchers continue to show that reducing levels of this microRNA allows autophagy to continue and protects neurons from death
.
In addition, they found that enhancing autophagy with a compound called G2 protected diseased neurons from death
.
As the researchers increased the dose of G2, the protective effect against cell death also improved
.

G2 is derived from a series of analogues found in the laboratories of David Perlmutter, M.
D.
, Executive Vice Chancellor for Medical Affairs, Deans of the School of Medicine George and Carol Bauer, and Distinguished Professors Spencer T.
and Ann W.
Olin; Gary Silverman, MD, Harriet B.
Spoehrer Professor and Head of Department of Pediatrics; and Dr.
Stephen C.
Pak
, Professor of Pediatrics in the Division of Neonatal Medicine.
G2 was identified by high-throughput screening of autophagy-enhancing drugs that correct cell accumulation of variants α-1-antitrypsin Z, which causes liver disease
in α-1-antitrypsin deficiency (ATD).
Thus, G2 compounds may be attractive candidates for preventing neurodegeneration in Huntington's disease, liver disease α-1-antitrypsin deficiency, and possibly other diseases in which the abnormal accumulation of misfolded proteins is toxic to cells
.

The study also reveals a potentially tantalizing clue
to understanding cognitive decline during normal aging.
When comparing symptomatic neurons with presymptomatic neurons and healthy neurons from young and old people, the researchers found that neurons in healthy older adults produced slightly elevated levels of harmful microRNAs, but far lower than those of
symptomatic Huntington's disease patients.
The study suggests that even during normal, healthy aging, mid-spiny neurons gradually produce low levels of this microRNA, which can interfere with healthy cell management
of autophagy.

"By modeling different stages of disease throughout the lifespan, we can determine how aging plays a role in disease onset," Yoo said
.
With this information, we can start looking for ways to
delay the onset.
Our study also suggests that triggers the onset of Huntington's disease may play a role
in age-related decline in general neuronal function.
Understanding the aging factors that contribute to neurodegeneration may help develop new strategies
to treat and prevent Huntington's disease and other neurodegenerative diseases of old age.
”

Yoo and his team are also working with other collaborators to use their cell reprogramming technique to study forms of Alzheimer's disease, psoriasis, and other neurodegenerative
diseases.