PRIMARY FACULTY

Xin Xiang, Ph.D.
Associate Professor
Biochemistry
 
4301 Jones Bridge Road
Bethesda MD 20814
Fax: 301-295-1996
Xin.Xiang@usuhs.edu
 
More about Dr. Xiang's Research

Xin Xiang, Ph.D.

Cytoplasmic dynein is a minus-end-directed microtubule motor important for intracellular trafficking of vesicles and proteins/mRNAs. Neurons are especially sensitive to dynein defects. In neurons, dynein is required for the long-distance retrograde transport of signaling endosomes containing survival factors, and dynein dysfunction results in neuronal degeneration observed in ALS (Amyotrophic lateral sclerosis) patients. Also, upon injury of peripheral neurons, dynein carries locally synthesized or activated injury factors towards the nucleus to activate transcription involved in a regenerative response. Our lab has been dissecting the regulatory mechanisms involved in dynein function using the filamentous fungus Aspergillus nidulans as a model system. In A. nidulans, dynein is required for nuclear distribution (nud) and retrograde endosome movement. Our genetic studies of the nud mutants have identified many proteins in the dynein pathway. These include the proteins in the previously isolated dynein accessory complex, dynactin, which is an elaborate multi-subunit complex whose backbone is a 37-nm filament containing Arp1 (Actin-related protein 1) subunits. Another important dynein regulator is LIS1, product of a causing gene for lissencephaly, a human brain disease manifested by mental retardation and severe epilepsy. The connection between LIS1 and dynein was first discovered in A. nidulans where we identified NUDF, a LIS1 homolog, in the dynein pathway. We have developed tools for imaging and biochemical studies on how these dynein regulators affect dynein localization and function. In the next few years, we will focus on investigating how NUDF/LIS1 and components of dynactin regulate dynein-mediated endosome movement. Specifically, we will ask whether these proteins regulate the binding of dynein to an endosome, the interaction between a dynein-bound endosome and its microtubule track, or the processive movement of the endosome along the microtubule track. We will continue to isolate novel regulators of dynein by cloning additional nud genes. Another project in the lab is to screen for drugs that may potentially benefit patients with ALS and lissencephaly. The distinct colony phenotype of the nud mutants allows a high-throughput screening for drugs that may compensate for the defects caused by mutations in NUDF/LIS1, dynein and dynactin. About 10% of the ALS cases are hereditary (familial) and a subset of which are caused by mutations in the superoxide dismutase or the SOD1 gene. In mice, a mild loss of dynein function attenuates the phenotype caused by a severe SOD1 mutation and increases the life span of the mutant. Thus, we will also screen for dynein inhibitors that may potentially benefit patients with SOD1-related ALS. The dynein inhibitors will also be great tools for studying dynein functions in mammalian cells, especially in neurons, where it is technically much more difficult to do the kind of genetic manipulations routinely done in fungi.

Selected Publications

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