Dr Mentis identifies key determinant of motor neuron dysfunction in a study part funded by SMA Europe
In a study partly funded through SMA Europe’s 6th Call for Research Proposals, Dr. George Mentis and his colleague Dr. Livio Pellizzoni, of the Motor Neuron Center at Columbia University in the US, identifies key determinant of motor neuron dysfunction induced by SMN deficiency in the motor circuit & thereby candidate targets for SMA therapy. The results of this study have been published in Cell Reports.
Motor neurons participate in the wiring system or motor circuits, which sends electrical impulses from the brain to the muscles, controlling how they contract and relax. A hallmark of SMA is the death of these motor neurons due to low levels of a protein called SMN, the causative role of the disease. However, in a mouse model of SMA, dysfunction in motor circuits as a whole is one of the earliest manifestations of the disease, as it precedes motor neuronal death. George Mentis, in collaboration with Livio Pellizzoni and their teams, have studied this dysfunction by looking at the communication between the different neurons that make up this circuit and its role in motor neuron death.
They addressed this by using a stem cell-based model of the motor circuit consisting of motor neurons and both excitatory and inhibitory interneurons, in which SMN protein levels were selectively depleted. They show that SMN deficiency induces selective motor neuron death through cell-autonomous mechanisms, while hyperexcitability is a non-cell-autonomous response of motor neurons to defects in pre-motor interneurons, leading to loss of glutamatergic synapses and reduced excitation. Findings from their in vitro model suggest that dysfunction and loss of motor neurons result from differential effects of SMN deficiency in distinct neurons of the motor circuit and that hyperexcitability does not trigger motor neuron death.
In conclusion, their findings point to premotor excitatory synapses as key determinants of motor neuron dysfunction induced by SMN deficiency in the motor circuit and are therefore candidate therapeutic targets for SMA. Furthermore, their stem cell-based model of the motor circuit provides a powerful platform to dissect the cascade of SMN-dependent events leading to death and dysfunction of motor neurons at the synaptic and molecular levels
Simon CM, Janas AM, Lotti F, Tapia JC, Pellizzoni L, Mentis GZ. A Stem Cell Model of the Motor Circuit Uncouples Motor Neuron Death from Hyperexcitability Induced by SMN Deficiency. Cell Rep. 2016 Aug 2;16(5):1416-30.