Written by Dr. Ambika Tewari Edited by Dr. Sriram Jayabal
Targeting phosphatases in the cerebellum can correct miscommunication in multiple models of ataxia.
The cerebellum is essential for motor coordination and consists of the coordinated activity of different types of cells. Purkinje cells are one of the most fascinating cell types in the cerebellum. They have an elaborate network of branches called dendrites, where a neuron receives communication from other neurons. It is one of the most complex branching systems seen across all neurons in the entire brain. Each one of these branches has many points of contact with other branches called axons. Each axon is part of a neuronal structure that allow communication between neurons. These axons are from different cell types and allow information to be transferred to Purkinje cells.
Due to this branching complexity, Purkinje cells receive many messages or inputs. This represents different pieces of sensory information to ensure that movements are precisely timed. Purkinje cells must integrate and process this information. This produces motor behaviors like walking, writing, playing a musical instrument, and many more. Any alteration to the processing of this information will result in cerebellum dysfunction; in fact, Purkinje cells have gained attention because they undergo progressive deterioration in most ataxias.
Neurons, including Purkinje cells, communicate with other neurons using electrical signals known as action potentials or spikes. Firing rate, defined as the number of spikes within a defined period of time, is thought to be an important feature of this communication, which is critical for coordinating muscle movements. Therefore, a lower firing rate in Purkinje cells would signal a faulty communication between Purkinje cells and their targets. This has devastating consequences as seen in many ataxias.
For instance, in an earlier study, a group of authors found that the firing rate of Purkinje cells was decreased in mouse models of three different Spinocerebellar ataxias (SCAs): SCA1, SCA2, and SCA5. They further explored whether there was a common reason underlying the decreased firing rate. They found that a protein named Missing in Metastasis (MTSS1), was important for Purkinje cells to effectively communicate with each other. Mice engineered to have no MTSS1 protein had a decreased firing rate and difficulty walking and maintaining their balance.
In every cell in the body, including brain cells, there are numerous proteins that perform different functions. The concerted effort of all are needed for the cell to perform its intended duty. Some of these proteins are maintained in the cell in an inactive form and are activated when they are required in the cell and inhibited when they are not. This highly regulated system aims to maintain precise levels of proteins in each cell, while simultaneously conserving energy. Each cell has many ways of activating/inactivating a protein. A specialized group of proteins known as kinases and phosphatases, adds and removes phosphate groups to and from proteins respectively, thereby altering their active/inactive forms which then changes their interactions with other proteins. MTSS1 is one such protein that inhibits the activity of a group of kinases known as Src family of non-receptor tyrosine kinases (SFKs).Continue reading “A new molecule identified that controls cerebellar communication”