In Rain Man's Synapses: Molecular consequences of autism mutations in the SHANK3 gene elucidated


An international team of researchers led by Dr. Michael R. Kreutz and Dr. Marina Mikhaylova from the Leibniz Institute of Neurobiology Magdeburg (LIN), the Center for Molecular Neurobiology Hamburg (ZMNH) and Humboldt University Berlin, and Dr. Eunjoon Kim from the Korea Advanced Institute of Science and Technology (KAIST) has deciphered the molecular-level effects of mutations in the autism risk gene SHANK3. The project was competitively funded by the Leibniz Association and has been published in the journal Elife.

Autism-related mutations result in the incorporation of incorrect amino acids (center and right: amino acids proline (P68) and cysteine (C12) highlighted in red), causing proteins to fold incorrectly and fail to maintain synaptic order.


In the 1988 road movie "Rain Man," Dustin Hoffman played an insular autistic man in one of his signature roles, adapted from the life of the most famous savant, Kim Peek. Autism is a complex developmental brain disorder associated with peculiarities in the perception and evaluation of sensory stimuli. Autistic people find it difficult to communicate and interact socially with others, often take refuge in stereotypical behavior patterns, and sometimes have cognitive problems or insular gifts.

Genetic mutations may be involved in the development of autism. The gene products affected are important proteins in the brain's synapses, such as the SHANK3 molecule. SHANK3 is a scaffold protein that contains many binding sites for other proteins and acts as a kind of master organizer for the postsynaptic protein machinery: It links transmitter receptors, signaling molecules, and the cytoskeleton and is indispensable for the precise work of synapses.


What are the effects of mutations found in autistic patients on the functioning of the SHANK3 protein? Michael Bucher, a doctoral student in the research groups of Michael R. Kreutz and Marina Mikhaylova, in close collaboration with Kim's lab from the South Korean Advanced Institute of Science and Technology, has recreated the defective proteins for two of these mutations using genetic engineering and analyzed their structure. Using biophysical techniques, the research team was able to demonstrate that the mutations lead to changes in the three-dimensional protein structure that have far-reaching consequences: The mutated SHANK3 proteins enter the synapses in the nerve cells less, which disrupts synaptic function.


"We were able to see that the mutations altered SHANK3 so that it could no longer organize the order and dynamics of proteins in excitatory synapses. This gave us a molecular deciphering of why patients carrying these mutations experience disruptions in synaptic connections that could be responsible for cognitive symptoms, for example," said Michael Bucher, first author of the study. In the next step, the mutated autism risk proteins will now be studied in mice to directly analyze the effects on behavior.



Source: Press Release Leibniz Institute for Neurobiology Magdeburg

Prof. Dr. Marina Mikhaylova
Humboldt-Universität Berlin
Institut für Biology

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