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DISC1 Aggregates Stall Intracellular Transport

9 February 2012. Proteins encoded by disrupted-in-schizophrenia 1 (DISC1) can clump together and slow the transport systems within a cell, according to a study published online on January 30 in Human Molecular Genetics. Led by Josef Kittler of University College London, U.K., the study also finds that aggregations of DISC1 protein can attract other, free-floating DISC1 proteins, presumably interfering with their function. The findings highlight the idea that problems with how DISC1 moves around in a cell may contribute to chronic mental illness.

Discovered in a Scottish family beset by schizophrenia and other mental illnesses over a decade ago, DISC1 has been linked to many biological processes, including neural differentiation and migration during brain development, and synapse formation and function (see SRF related news story). While risk-associated alleles for DISC1 could alter any one of these functions to increase susceptibility to mental illness, yet another idea has emerged based on the ability of DISC1 proteins to bind to each other: “DISCopathy,” in which the aggregation of DISC1 is pathogenic, similar to the more famous protein pathologies involved in neurodegenerative diseases like Alzheimer’s (Korth, 2009).

Evidence for this stems largely from postmortem work, which has found DISC1 to be enriched in the insoluble protein fraction—which contains aggregated, non-functional protein—recovered from brains of individuals with schizophrenia, depression, and bipolar disorder compared to controls (Leliveld et al., 2008). Though corresponding DISC1 aggregates were not detected by microscope, the study found that aggregation could inhibit binding between DISC1 and one of its binding partners, NDEL1. Along with genetic studies showing that variants in HSP70, a chaperone that helps guide protein folding, are associated with schizophrenia (Kim et al., 2008) and bipolar disorder (Pae et al., 2009), these findings suggest that faulty DISC1 trafficking within the cell could contribute to mental illness.

Aggregates in aggresomes
The new study delves deeply into the cell biology to get at just what DISC1 aggregates are doing in the cell: are they inert bystanders, or do they get in the way of things? First author Talia Atkin and colleagues overexpressed GFP-tagged DISC1 protein in COS7 cells, and found large DISC1 aggregates over 5 microns in diameter formed in about 30 percent of cells. Though these types of aggregates have been found before, Atkin and colleagues further localized these clumps to the aggresome, a membrane-bound compartment that houses proteins and organelles destined for destruction. Similar results were obtained in cultured neurons.

Consistent with this aggresomal location, the DISC1 aggregates colocalized with a marker for the autophagy pathway, which disposes of the cell’s garbage. Furthermore, compounds that inhibit autophagy increased the number of cells with DISC1-containing aggresomes. Finally, playing with the different garbage disposal pathways in the cell could shift the prevalence of DISC1 aggregates. For example, inhibiting the proteasomal pathway, which uses a multiprotein proteasome complex to degrade defunct or unneeded proteins one at a time, led to more cells with DISC1-containing aggresomes. Conversely, treating cells with enhancers of the proteasomal pathway decreased the number of cells with large DISC1-containing aggregates.

Turning to rat cortical neurons, the researchers used the same methods employed in the postmortem studies to recover the insoluble proteins from cultured neurons. These contained a low level of DISC1, including a 72 kD isoform linked to aggregate formation in the postmortem study, but could be prodded to incorporate more DISC1 under free radical-enriched conditions. Applying the same technique to COS7 cells containing aggresomal GFP-DISC1, the researchers found much of this DISC1 in the insoluble fraction, thus drawing a link between aggresomes in these cells and the insoluble fraction obtained in postmortem studies.

Dead end
These DISC1 aggregates had effects beyond the aggresome. First, the DISC1 aggregates seemed able to sequester soluble, free-floating DISC1 proteins to the aggresome: overexpressing DISC1 in COS7 cells increased the amount of endogenous DISC1 in the insoluble fraction by a factor of three, and reduced the endogenous DISC1 in the soluble fraction by nearly half. Fluorescent recovery after photobleaching experiments combined with live cell imaging revealed that, once recruited to the aggresome, DISC1 did not return to the cytosol, where it is needed to carry out its functions. DISC1 aggregates were also immobile, unlike smaller clusters that moved at a velocity typical for other cargo. These findings suggest that the DISC1 aggregates are a dead end, containing DISC1 that is of no use to the cell.

To see if depletion of soluble DISC1 has consequences, the researchers monitored intracellular transport, something that DISC1 regulates. With live cell imaging, the researchers found that cells containing DISC1 aggresomes did not transport mitochondria within the axons of hippocampal neurons as readily as control neurons. While only 13 percent of mitochondria moved in neurons transfected with GFP-DISC1, 24.4 percent of mitochondria moved in control neurons transfected only with GFP. This suggests that DISC1 in aggresomes somehow interferes with cargo transport within the cell.

If perturbing non-mutant DISC1 trafficking can disrupt intracellular transport, what could risk-associated forms of DISC1 do? A chimeric protein resembling something that might result from the original Scottish translocation aggregates (Zhou et al., 2010) and other risk variants also results in DISC1 aggregates (Narayanan et al., 2011; Leliveld et al., 2009). Further experiments will have to examine the full spectrum of consequences in neurons containing these kinds of DISC1 aggregates to fully grasp the implications for mental illness.—Michele Solis.

Atkin TA, Brandon NJ, Kittler JT. Disrupted in Schizophrenia 1 forms pathological aggresomes that disrupt its function in intracellular transport. Hum Mol Genet. 2012 Jan 30. Abstract

Comments on Related Papers
Related Paper: Convergence of two independent mental disease genes on the protein level: recruitment of dysbindin to cell-invasive disrupted-in-schizophrenia 1 aggresomes.

Comment by:  T.A. AtkinJosef Kittler
Submitted 13 June 2011 Posted 13 June 2011

Protein aggregation is a well-characterized disease...  Read more

View all comments by T.A. Atkin
View all comments by Josef Kittler

Related Paper: Convergence of two independent mental disease genes on the protein level: recruitment of dysbindin to cell-invasive disrupted-in-schizophrenia 1 aggresomes.

Comment by:  Carsten Korth, SRF Advisor
Submitted 14 June 2011 Posted 14 June 2011

These are valuable comments, and I would agree in seeing...  Read more

View all comments by Carsten Korth
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