Depression, schizophrenia, Alzheimer's and other neurological diseases do not treat women and men equally. For reasons that are not yet known, the prevalence of these diseases - and sometimes even their symptoms - differ between the sexes. Recently, Weizmann Institute of Science scientists compared neural networks of female and male worms, and discovered a molecular mechanism that may explain how differences between the sexes in neurological diseases in humans arise
Depression, schizophrenia, Alzheimer's and other neurological diseases do not treat women and men equally. For reasons that are not yet known, the prevalence of these diseases - and sometimes even their symptoms - differ between the sexes. Recently, Weizmann Institute of Science scientists compared neural networks of female and male worms, anddiscovered a molecular mechanism which may explain how gender differences arise in neurological diseases in humans.
The tiny worm Caenorhabditis elegans is an excellent model for studying neural networks in the brain, since its nervous system is relatively simple, and it is the only organism so far in which all the neural connections in its brain have been mapped - in both sexes. When the worms come into the world, there is no difference in the neural connections between females and males - and these emerge only when they reach sexual maturity. Dr Mittal Oren-Suisa From the Department of Neurobiology and its research group hypothesized that identifying the mechanisms responsible for the appearance of these differences will help shed light on brain differences between men and women, and in particular differences related to neurological disorders.
In experiments led by staff scientist Dr. Yehuda Salzberg, the scientists focused on the connection between two nerve cells that allow the worm, similar to sensory cells in humans, to sense its environment. Before they reach sexual maturity, this connection exists in both females and males, but after that - the connection disappears in females and is preserved in males; In this context it is worth noting that the female worm is indeed defined as a hermaphrodite, since she produces both eggs and sperm, but genetically her nervous system is female.
Dr. Salzberg and his colleagues examined several possible mechanisms leading to the removal of connections between nerve cells and discovered that in adult females, a well-known molecular tag called ubiquitin is responsible for removing the particular connection they studied. This tag - whose functions include marking proteins for breakdown and recycling and participating in the design of neural networks in embryos - is found in living beings along the length and breadth of the evolutionary tree, including humans.
Later, the scientists revealed how the connection is removed at the molecular level. They conducted experiments on genetically modified worms and discovered that an E3 enzyme, which is also found in humans and plays a central role in the ubiquitin system, marks an important receptor called DCC on the surface of the nerve cell as "destined for destruction", and this with the help of the ubiquitin tag. At this point, it became clear to the researchers why the connection disappeared only in females. In males, the degradation of the DCC receptor is blocked by the secretion of a biochemical signal called netrin, which prevents the binding of E3 to DCC. On the other hand, in females, the neuron does not secrete netrin, so the E3 is free to bind to the DCC and mark it for destruction - and with it the entire connection. When the scientists prevented the destruction of the receptor, female worms maintained the connection between the nerve cells, and their neural circuit was identical to that of the males.
Is the DCC receptor the key to understanding sex differences in neurological diseases in humans? Many studies have shown a connection between certain versions of the gene encoding this receptor and between clinical depression, schizophrenia, bipolar disorder, autism and other diseases, the common denominator of which is that their prevalence is different in men and women - and sometimes even their symptoms are different. The new role of the receptor discovered in the current study points to a new research direction that may make it possible to uncover molecular mechanisms responsible for gender differences in neurological diseases. Revealing the mechanisms may in turn pave the way for the development of drugs that are specifically adapted to women or men.
The research students Valdislava Patchuk, Assaf Gat, Hagar Seti and Sapir Sela from the laboratory of Dr. Oren-Suissa participated in the study.
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