Hereditary spastic paraplegia (HSP) is a group of inherited neurological disorders that cause progressive spasticity and weakness in the lower extremities. Mutations in the atlastin-1 gene, one of the major mutational hot spots in the disease, account for ~10% of autosomal dominant HSP cases (subtype SPG3A), and for the majority of cases in infants or children. Defects in this protein results in axonal degeneration in unique sets of neurons, in this case upper motor neurons, yet the molecular mechanism is poorly understood. Atlastin-1 belongs to the dynamin superfamily of large G-proteins, members of which participate in diverse cellular functions, including endocytosis, organelle fusion and fission, cytokinesis, and antiviral activity. On a cellular level, atlastin-1 is involved in generating the tubular endoplasmic reticulum (ER) network by facilitating homotypic membrane fusion. Those dynamin-related G proteins that catalyze homotypic fusion of biological membranes comprise a small minority of this family, and have not been characterized extensively in their structure-function relationship. Structural characterization as well as investigation of partner protein interactions will provide key insights into how and why defects in atlastin-1 result in its pathogenic effects. The first objective will be the structural characterization of atlastin-1 along the nucleotide hydrolysis cycle.
This aim will also include the structure determination of HSP-associated mutant variants of the protein in order to reveal pathogenic mechanisms.
The second aim focuses on a functional characterization of atlastin-1 mutants using biochemical and biophysical approaches. These studies will complement the crystallographic analyses. By conducting thorough structure-function analyses of wild-type and mutant atlastin-1 variants, a molecular mechanism for disease pathogenesis can be derived, which may provide better means with regard to disease prognosis and intervention.
There is an emerging theme that neurological disorders are caused or affected by defects in membrane structure and trafficking, exemplified by hereditary spastic paraplegia. However, the underlying molecular mechanisms often remain enigmatic. Structure-function analyses of the affected proteins and their mutant variants will lead to a deep understanding of disease pathogenesis and may provide novel avenues for disease management and treatment.
| O'Donnell, John P; Byrnes, Laura J; Cooley, Richard B et al. (2018) A hereditary spastic paraplegia-associated atlastin variant exhibits defective allosteric coupling in the catalytic core. J Biol Chem 293:687-700 |
| Byrnes, Laura J; Singh, Avtar; Szeto, Kylan et al. (2013) Structural basis for conformational switching and GTP loading of the large G protein atlastin. EMBO J 32:369-84 |
