Gaining Unexpected Insights Into Hereditary Spastic Paraplegia
Sprouting. Branching. Pruning. Neuroscientists have borrowed heavily from botanists to describe the way that neurons grow, but analogies between the growth of neurons and plants may be more than superficial. A new study from the National Institutes of Health and Harvard Medical School suggests that neurons and plant root cells may grow using a similar mechanism.
The research also sheds light on the hereditary spastic paraplegias (HSP), a group of inherited neurological disorders in which some of the longest neurons in the body fail to grow and function properly. The genes behind HSP and their roles inside neurons are poorly understood. However, the study suggests that several forms of HSP share an underlying defect with each other — and with abnormal root hair development in a plant widely used for agricultural research.
The strange implication is that the plant, Arabidopsis thaliana (mouse-ear cress), could prove useful for further research on HSP.
"This study provides us with valuable new insights that will stimulate research toward therapies for hereditary spastic paraplegias," says Craig Blackstone, M.D., Ph.D., an investigator at NIH's National Institute of Neurological Disorders and Stroke (NINDS) and an HSP expert. Dr. Blackstone performed the study in collaboration with William Prinz, Ph.D., an investigator at the NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and Tom Rapoport, Ph.D., a Howard Hughes Medical Institute investigator and a professor of cell biology at Harvard Medical School.
HSP primarily affects corticospinal neurons, which extend projections called axons from the brain's cerebral cortex to the spinal cord. The longest corticospinal axons extend nearly all the way down the spinal cord — a distance up to about three feet — in order to control movement in the legs. In HSP, these long axons develop abnormally or they degenerate later in life, causing muscle stiffness and weakness in the legs. HSP exists in many forms in different families, and more than 40 genes have been implicated in the disease.
In the new study, published in Cell, the researchers propose that defects in the shaping of a subcellular structure known as the endoplasmic reticulum (ER) are a common cause of HSP. The ER — named for its reticulated (or net-like) shape — is a cellular factory, where molecules such as proteins and lipids that are vital to cell growth are made and packaged for shipping to various cellular destinations. The researchers theorize that in several forms of HSP, the ER loses its complex shape and is unable to support the growth or maintenance of long corticospinal axons.
Several years ago, other researchers showed that similar ER defects in Arabidopsis impair the growth of the plant’s root hairs. These are wispy, microscopic projections that grow from the plant’s individual root cells.
The new study focuses on a gene called atlastin. This gene is defective in about 10 percent of HSP cases, and in previous research, Dr. Blackstone's group showed that it has a role in axon growth. The new study reveals that the atlastin protein is necessary for maintaining the shape of the ER in mammalian cells, and that an analogous protein called Sey1p performs the same function in baker's yeast.
The researchers demonstrate that ER shaping defects have general relevance for HSP, by showing a connection between atlastin and a group of proteins known as the DP1 family. Years ago, Drs. Prinz and Rapoport reported that a yeast analog of DP1 regulates the shape of the ER in yeast. Meanwhile, others researchers had independently reported that mutations in REEP1, a member of the DP1 family, cause 3 percent to 8 percent of HSP cases. The new study shows that atlastin interacts physically with DP1 in mammalian cells, and that Sey1p (the yeast atlastin) interacts with the DP1 analog in yeast.
Finally, Dr. Blackstone's study notes that Arabidopsis has an analog of atlastin, called Root Hair Defective 3 (RHD3). Mutations affecting RHD3 cause the plant to grow short, wavy root hairs.
If this connection between axon growth and root hair growth withstands further study, Arabidopsis could be a useful tool for investigating mechanisms of HSP. Arabidopsis is easy to raise in the lab, and the short root hairs of the RHD3 mutant are easy to observe, compared to the growth defects in atlastin-deficient neurons and yeast. Dr. Blackstone hopes to collaborate with other researchers to initiate a search for genes and compounds that correct root hair development in the RHD3 mutant, which might provide valuable therapeutic insights into HSP.