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Funded Studies

Functional Evaluation of Alpha-synuclein Dosage Effects in CRISPR‐edited SNCA Model

Promising Outcomes of Original Grant:
The goal of our original grant was to develop a patient-derived stem cell model from skin cells with different expression levels of protein alpha-synuclein, which is known to be implicated Parkinson’s pathology. We successfully derived and characterized a panel of stem cell lines with genetically “inactivated” alpha-synuclein gene copies using novel gene editing technologies. The cell lines express alpha-synuclein corresponding to the number of functional copies in the alpha-synuclein gene. Differentiated neuronal cells from these cell lines showed differences in the composition of Parkinson’s specific neuronal markers.

Objectives for Supplemental Investigation:
The objectives of the supplemental investigation are to derive additional cell lines to address variability of the cell model system, to characterize potential off-target effects of genetic engineering, and then assess the functional outcomes of various levels of endogenous alpha-synuclein in these cells lines when differentiated into mature neurons. More specifically, we will quantify levels of midbrain transcription marker, neuronal and glia markers in differentiated neuronal cultures in all cell lines ranging from no alpha-synuclein expression (0 functional alpha-synuclein gene copies) to 2-fold overexpression (4 functional alpha-synuclein gene copies). Furthermore, we will assess cytotoxicity, mitochondrial health, autophagy and neuronal network activity in these cell cultures. All cell lines will be banked and made available and distributed to the research community at the end of the study.

Importance of This Research for the Development of a New PD Therapy:
Alpha-synuclein has also become a leading target for the development of new therapies aimed at slowing or stopping disease progression. These observations have led to a wide-spread consensus that lowering the alpha-synuclein content and/or eliminating toxic alpha-synuclein species in cells could be a successful approach to slowing, reversing, or even preventing Parkinson’s disease or related alpha-synucleinopathies. Our unique cell model system of different alpha-synuclein gene copies at the endogenous gene locus will be useful for the study the effects of alpha-synuclein when overexpressed or reduced. This cell model will be important for drug screening and development for alpha-synuclein-modifying therapies in PD.


  • Birgitt Schüle, MD, Dr. med.

    Stanford, CA United States

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