Synaptopathies: diseases of the synaptome

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• The human synapse proteome is highly complex and disrupted by numerous gene mutations, leading to over 100 brain diseases known as synaptopathies.
• Synaptopathies manifest as psychiatric, neurological, and developmental disorders, arising from both Mendelian and complex genetic factors.

Purpose of the Study:

• To analyze the human postsynaptic proteome and its core signaling complexes, particularly those involving Membrane Associated Guanylate Kinase (MAGUK) scaffold proteins.
• To establish a systematic approach for understanding synaptic diseases and their underlying molecular mechanisms.

Main Methods:

• Investigated the role of MAGUK Associated Signaling Complexes (MASC) in human diseases like Autism, Schizophrenia, and Intellectual Disability.
• Utilized mouse models with orthologous mutations to study cognitive, social, and motor phenotypes relevant to human synaptopathies.

Main Results:

• Mutations in MASC are linked to a spectrum of neurodevelopmental and psychiatric disorders.
• Mouse models carrying these mutations exhibit phenotypes mirroring human disease symptoms, validating the conserved role of these complexes.
• Disruption of synaptic protein complexes and their interactors results in diseases with overlapping phenotypes and symptom profiles.

Conclusions:

• The study proposes a novel brain disease classification system based on molecular etiology and pathogenesis.
• Classifying synaptic disease phenotypes using genetic and proteome data provides a more precise understanding of brain disorders.