Direction 1. Mechanisms of NMNAT-mediated neuroprotection.
Neurodegeneration occurs in numerous neurological diseases and conditions including stroke. Although the precise cause is often unknown, many neurodegenerative conditions share common features such as protein aggregation and age dependence. Dr. Zhai’s team was the first to identify NMNAT as a neuronal maintenance factor in Drosophila retina, mutations in which were later identified in human to cause Leber congenital amaurosis (LCA9), an early onset retinal degeneration. Dr. Zhai’s team studies in Drosophila have uncovered protective effects of NMNAT against activity-induced neurodegeneration, injury-induced axonal degeneration, spinocerebellar ataxia 1 (SCA1)-induced neurodegeneration, and Tauopathy, suggesting a general neuroprotective function of NMNAT. Their biochemical and cellular analyses further uncovered a novel chaperone function of NMNAT and its endogenous synaptic client/target. They found that NMNAT protects against protein aggregation-induced neurodegeneration through a proteasome-mediated pathway in a manner similar to heat-shock protein 70 (Hsp70) that is independent of mitochondria function. These studies uncovered a novel neuroprotective process and established NMNAT as one of the most robust and versatile neuroprotective factors identified so far.
Direction 2. Functional analysis of neurological phenotypes in Drosophila models of rare and common neurological diseases.
Dr. Zhai’s lab is dedicated to taking full advantage of the Drosophila genetic model systems to understand human (rare) genetic diseases.
In collaboration with NIH Undiagnosed Disease Program (UDP), they have carried out a pilot functional screen in Drosophila of the mutant variants identified in UDP and facilitated the confirmation of 11 disease-causing genes, 4 out of which are new diseases. Specifically, Dr. Zhai’s team established Drosophila models for several rare diseases, including a model for a novel variant that causes nonsyndromic deafness; and a model for Snyder-Robinson Syndrome (SRS), and further carried out more in-depth functional analysis and developed a new research direction (Direction #3). For common neurological diseases, we recently established a model of chemotherapy-induced peripheral neuropathy (CIPN) and characterized the mechanisms of paclitaxel-induced sensory dysfunction.
It is important to note that our work was pivotal to the success of NIH-UDP program and served as the basis for the expansion of the UDP to UDN (undiagnosed disease network).
Direction 3. Mechanisms of mitochondria function and polyamine metabolism in rare neurological diseases.
Dr. Zhai’s lab is interested in understanding the role of metabolic pathways in the pathogenesis of several neurological diseases in vivo using Drosophila models. They have established a model for Snyder-Robinson Syndrome (SRS), an X-linked intellectual disability syndrome caused by loss-of-function mutations in spermine synthase (SMS), a polyamine biosynthesis enzyme. They also carried out more in-depth functional analysis and discovered an important mechanism underlying the neurotoxicity of polyamine oxidation. Specifically, Dr. Zhai found that SMS deficiency leads to excessive spermidine catabolism, which generates toxic metabolites that cause lysosomal defects and oxidative stress that compromise autophagy-lysosome flux and mitochondrial function in the Drosophila nervous system and SRS patient cells. Currently, they are funded to explore mechanistically the mitochondria toxicities in SRS and other polyamine-associated neurological disorders.
Because of the innovative nature of our work, Dr. Zhai is continually developing new methods to facilitate and enable our functional characterization of phenotypes highly relevant to human neurodegenerative diseases. These include the establishment of relevant behavior assays, biochemical analysis of protein aggregation, and imaging of the nervous system with single-cell resolution.