Graduate Studies Faculty
Vivek K. Unni, M.D., Ph.D.
Programs:Neuroscience Graduate Program
Research Interests:Parkinson’s Disease, alpha-synuclein, protein aggregation and degradation, neurodegeneration, in vivo imaging, clinical neurology, movement disorders
Preceptor RotationsDr. Unni has not indicated availability for preceptor rotations at this time.
Faculty MentorshipDr. Unni has not indicated availability as a mentor at this time.
One hypothesis for how this could occur is that increased alpha-synuclein levels by itself causes this protein self-aggregate to form potentially toxic species that then cause neurons to die. This simple scenario is complicated, however, by the fact that alpha-synuclein can form many different kinds of aggregates, some of which are potentially toxic and others which could be protective. The ability to test this and related hypotheses in the living brain would greatly benefit from the development of new experimental strategies to visualize alpha-synuclein in vivo, its metabolism, aggregation and the consequences of these processes for neurons. For these reasons I have spent the past several years, first at Harvard Medical School and Massachusetts General Hospital and now at OHSU, developing new approaches to try and tackle these difficult problems. Our work allows us (for the first time) to visualize alpha-synuclein in the living brain in mouse models of PD and DLB using in vivo multiphoton fluorescence microscopy through “cranial windows.”
Our recent data demonstrate that we can visualize human wild-type alpha-synuclein fused to enhanced Green Fluorescent Protein in the cortex of transgenic mice with cellular and synaptic resolution using this cranial window-based approach. Furthermore, we can follow individually labeled neurons or presynaptic terminals serially over a period of many months and obtain measurements of alpha-synuclein mobility in vivo in these compartments. We have also developed treatment paradigms for applying agonists or antagonists of different relevant pathways directly to the cells that are being imaged in vivo and for recovering treated tissue in order to do further biochemical analysis. Using these approaches, we are currently studying the mechanisms of alpha-synuclein aggregation and degradation in the living brain. Specifically, we have been probing the role of the two main protein degradation pathways known, the ubiquitin-proteasome system and autophagy, in the degradation of alpha-synuclein in vivo, currently an unanswered question in the field. In addition, we are studying the role of environmental toxins implicated in PD pathogenesis on the aggregation of alpha-synuclein in vivo and the subsequent neuronal dysfunction this causes.
Ebrahimi-Fakhari D, Cantuti-Castelvetri I, Fan Z, Rockenstein E, Masliah E, Hyman BT, McLean PJ and Unni VK. (2011) Distinct roles in vivo for the ubiquitin-proteasome system and the autophagy-lysosomal pathway in the degradation of α-synuclein. J Neurosci, 31:14508-14520.
Unni VK, Ebrahimi-Fakhari D, Vanderburg CR, McLean PJ and Hyman BT (2011). Studying protein degradation pathways in vivo using a cranial window-based approach. Methods Mar; 53(3):194-200.