Creating neurons from skin cells to understand autism

By Robin Marks  |  Originally published on UCSF News
 

Studying brain disorders is complicated for many reasons, not the least being the ethics of obtaining living neurons. To overcome that obstacle, UC San Francisco postdoc Aditi Deshpande, PhD, is starting with skin cells.

Thanks to developments in stem cell technology, new information about the human brain is now being gleaned from a simple cheek swab or skin sample. This technology is key to the kind of progress Despande and researchers like her are making. It allows them to work with cells otherwise unobtainable – living brain cells that have the same genetics as the patients.

Deshpande begins with skin cells obtained from the Simons Foundation from volunteers whose DNA contains a specific deletion or duplication of one chromosome. She cultures these cells and then turns them into induced pluripotent stem cells – cells that have been coaxed back to their embryonic state and are able to become any other type of cell. From there, she reprograms them to become a specific type of neuron that’s involved in attention and information processing.

Neurons

Human neurons that were derived from skin cells.  [Image courtesy Aditi Deshpande]

Where the deletion, duplication occurs

The deletion or duplication Deshpande is looking for stems from a 2008 finding by Lauren Weiss, PhD, an associate professor of neurology in the UCSF Department of Psychiatry and the UCSF Institute for Human Genetics.

Weiss discovered a 29-gene region of DNA on chromosome 16 that is associated with autism, seizures, and other brain disorders. Normally, a person has two copies of the region – one on each copy of chromosome 16. In some of Deshpande’s samples, the region is deleted from one chromosome, leaving one copy. In others, the region is duplicated, resulting in three copies. Subjects with only one copy of the region were more likely to have macrocephaly – an enlarged brain – than a typical subject, and those with three copies were more likely to have microcephaly – a smaller brain.

“What’s really interesting,” said Deshpande, “is that although these subjects seem to have opposite features in terms of brain size, we see a related effect, based on whether they have fewer or more copies of the region.”

Some known models of autism show a connection between a neuron’s growth or appearance and macrocephaly, she explained. “We wanted to know if the same thing is happening here.”

Assessing several thousands of neurons

To compare the effect of the mutation, Deshpande first stains the obtained skin cells so that she can visualize the neurons under a microscope. After staining, Deshpande used cell-counting software to assess several thousands of neurons from deletion and duplication samples and measure them against normal neurons. She found that the neurons missing the DNA region exhibited some differences compared to typical neurons.

Her next step in her research is to discern which of the region’s 29 genes are involved in these differences.

The work is meticulous, but Deshpande doesn’t mind. “I simply love looking at neurons,” she said. “It really makes you appreciate the complexity of the brain.”


About UCSF Psychiatry

The UCSF Department of Psychiatry and the Langley Porter Psychiatric Institute are among the nation's foremost resources in the fields of child, adolescent, adult, and geriatric mental health. Together they constitute one of the largest departments in the UCSF School of Medicine and the UCSF Weill Institute for Neurosciences, with a mission focused on research (basic, translational, clinical), teaching, patient care and public service.

UCSF Psychiatry conducts its clinical, educational and research efforts at a variety of locations in Northern California, including UCSF campuses at Parnassus Heights, Mission Bay and Laurel Heights, UCSF Medical Center, UCSF Benioff Children's Hospitals, Zuckerberg San Francisco General Hospital and Trauma Center, the San Francisco VA Health Care System, and UCSF Fresno.

About the UCSF Weill Institute for Neurosciences

The UCSF Weill Institute for Neurosciences, established by the extraordinary generosity of Joan and Sanford I. "Sandy" Weill, brings together world-class researchers with top-ranked physicians to solve some of the most complex challenges in the human brain.

The UCSF Weill Institute leverages UCSF’s unrivaled bench-to-bedside excellence in the neurosciences. It unites three UCSF departments—Neurology, Psychiatry, and Neurological Surgery—that are highly esteemed for both patient care and research, as well as the Neuroscience Graduate Program, a cross-disciplinary alliance of nearly 100 UCSF faculty members from 15 basic-science departments, as well as the UCSF Institute for Neurodegenerative Diseases, a multidisciplinary research center focused on finding effective treatments for Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease, and other neurodegenerative disorders.

About UCSF

UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises top-ranked hospitals – UCSF Medical Center and UCSF Benioff Children’s Hospitals in San Francisco and Oakland – and other partner and affiliated hospitals and healthcare providers throughout the Bay Area.