engleski

DISC1 and FUS: linking proteins from mental and neurodegenerative illnesses through aggregation

Chronic mental illnesses, such as schizophrenia, bipolar disorder, or depression, have overlapping genetic backgrounds and symptoms. These illnesses are manifested as disruptions of mental health (cognitive, emotional, and behavioral) from various etiological factors. Neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) or Alzheimer’s disease are well known to be associated with occurrence of protein aggregation. Recent studies suggest that this same biological state, in which misfolded proteins aggregate, may be found in mental illnesses as well. The Disrupted in Schizophrenia 1 (DISC1) protein has been identified in protein aggregates from the brain tissue of patients suffering from schizophrenia, bipolar disorder, and depression. We are investigating the interaction of DISC1 with the Fused in Sarcoma protein (FUS) in protein aggregates. FUS has been found in protein aggregates of various neurodegenerative illnesses, including ALS and frontotemporal dementia (FTD). This interaction, therefore, provides an interesting biological link between mental illnesses and neurodegenerative disorders. We compared wild-type and mutated FUS protein with DISC1 in cultured mammalian cells. Microscopic examination of cells overexpressing these two proteins showed them to co-aggregate. Mutations of FUS protein have been described as contributing to neurodegenerative disorders, and in this case, only mutated FUS co-aggregated with DISC1. Additionally, we examined co-aggregation of fragments of DISC1 with the FUS protein, in order to determine which domains of this protein are involved in co-aggregation. From the data we obtained so far, we can conclude that co- aggregation of DISC1 and FUS protein is dependent on C-terminal regions of DISC1. These results can help explain biological connections between neurodegenerative disorders and mental illnesses while explaining aspects of the overlap in symptoms of these illnesses and the difficulty of making specific diagnoses.

Amyotrophic Lateral Sclerosis ; Mental Disorders ; Neurodegenerative Diseases ; Protein Aggregates ; Schizophrenia

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