Investigator:
Anastasia Kuzkina, MD
Name of Institution:
Brigham and Women’s Hospital/Harvard Medical School, Boston, MA
Project Title:
Developing human iPSC models for examining host-strain interactions in synucleinopathy
Investigator Bio:
Dr. Kuzkina is a postdoctoral researcher in the laboratory of Dr. Vikram Khurana of the Division of Movement Disorders at Brigham and Women’s Hospital. Dr. Kuzkina received her MD degree from the Sechenov Medical University of Moscow, Russia, and continued her Neurology training at the University Hospital in Würzburg, Germany, where she also obtained an M.Sc. Her clinical and research interests relate to neurodegenerative disorders, focusing on Parkinson’s disease (PD) and Multiple system atrophy (MSA). During her graduate and early postgraduate work, she studied α-synuclein as a biomarker, focusing on its aggregation in the peripheral nervous system, such as dermal and olfactory nerves.
Objective:
To investigate different strains of α-synuclein and the variability in their aggregation and toxicity in different brain cell types.
Background:
α-synuclein aggregation is widespread throughout the nervous system in neurodegenerative diseases called synucleinopathies. There are however, disease-specific differences in the types of brain cells affected in different synucleinopathies such as PD and MSA. A growing literature suggests that the differences in cell vulnerability could be due to the distinct propensity of specific amyloid “strains” of α-synuclein to aggregate and perturb biology in distinct cell types. My project will use induced pluripotent stem cells (iPSCs), human stem cells created from adult tissue such as skin, that will be grown into different brain cells and exposed to patient-derived α-synuclein in order to closely represent the disease process in the human body. We will examine to what extent the intrinsic properties of α-synuclein are responsible for selective cellular pathologies seen in PD and MSA and to what extent the type of host cell is responsible for these differences.
Methods/Design:
I will use α-synuclein aggregates generated from PD and MSA patients and introduce them into different types of brain cells made in our lab. We will start with trying to understand how the different aggregates affect the cortical neuron, a type of neuron that is affected in all synucleinopathies. Thereafter, we will study the various aggregates in other types of neurons. The Khurana lab has made inroads into the challenging task of making “pure” neuron populations by introducing a “reporter” for different types of relevant neurons, including dopamine-secreting neurons in the midbrain or gut and norepinephrine-secreting neurons in the skin or heart. This will enable us to study α-synuclein in diverse cell types representing different parts of the nervous system and to understand the reasons for their differential involvement in PD and MSA.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
By systematically analyzing the effects of different α-synuclein aggregates in different brain cells, we will gain insight into the disturbances in biology that underlie different synucleinopathies. Our system, closely modeling the pathology seen in patients, could also help us understand for which disease a treatment is likely to be effective, and thereby facilitate development of tailored therapies.