Summary: A protein called Scribble (SCRIB gene) appears to orchestrate the intracellular signaling process for forgetting, a new study reports.

Source: University of Edinburgh.

aging-brain

More than one thousand people have had their entire genetic make-up decoded as part of a long-term study to gain insight into why some people’s brains age better than others.

Scientists in Edinburgh have sequenced the DNA of more than 1300 people taking part in a decades-long study into ageing and memory.

The development will enable in-depth analysis of the genetic make-up of those taking part, and may help to identify the genetic basis of why some people’s brains age better than others.

Memory study

The Lothian Birth Cohorts comprise two groups of people born in 1921 and 1936, who were tested on their mental abilities at age 11, originally as a way of informing education policy.

Over the past 15 years, members of the cohort have been regularly tested by researchers at the University of Edinburgh’s Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE).

Aging brain

Their follow-up mental examinations, blood tests and brain scans have yielded a trove of valuable information on mental and physical ageing.

Genome sequencing

Now, researchers have decoded the entire genetic make-ups of those taking part. By linking this genetic information with the cognitive testing carried out over the past 15 years, researchers hope to shed new light on the factors underlying healthy ageing.

“This genetic data will prove invaluable for understanding why some people’s brains and thinking skills age better than others. The flip side of having such comprehensive genetic data is that we will also understand better how the environment and lifestyle choices can contribute to healthy ageing” said Professor Ian Deary, Director, Centre for Cognitive Ageing and Cognitive Epidemiology.


 

Brain scans carried out by researchers in the Division of Psychiatry have revealed how a genetic mutation linked to major psychiatric disorders affects the structure, function and chemistry of the brain.

Brain scans have revealed how a genetic mutation linked to major psychiatric disorders affects the structure, function and chemistry of the brain.

CCBS researchers in the Division of Psychiatry led a team who scanned the brains of people who have a translocation mutation in the DISC1 gene. This mutation is associated with schizophrenia, bipolar disorder and recurrent major depression.

The team found that people with the mutation had changes in brain structure of their brain. These changes were linked with the severity of their symptoms of mental ill health. They also showed that carriers of the mutation had lower levels of glutamate in certain areas of their brain. Reduced glutamate levels have been strongly linked with schizophrenia in previous studies.

These findings confirm that the DISC1 mutation is associated with a significantly increased risk of psychiatric illness. Continuing to study people with the mutation will likely reveal new insights to the biological mechanisms that underpin these conditions.

This study confirms and extends the genetics of DISC1, and shows how that and similar genetic effects can increase the risk of major mental illnesses.

Professor Stephen LawrieHead of the Division of Psychiatry, CCBS

Family history

The DISC1 mutation was first identified in a Scottish family that showed unusually high rates of major psychiatric disorders. Scientists have been studying generations of the family for 40 years but this is the first time they have scanned their brains.

Study

The study is published in the Nature partner journal Schizophrenia and was funded by the Translational Medicine Research Collaboration – a consortium of Scottish universities and NHS Health Boards, Scottish Enterprise and Pfizer.


Disrupted in schizophrenia 1 is a protein that in humans is encoded by the DISC1 gene.[3] In coordination with a wide array of interacting partners, DISC1 has been shown to participate in the regulation of cell proliferation, differentiation, migration, neuronal axon and dendrite outgrowth, mitochondrial transport, fissionand/or fusion, and cell-to-cell adhesion. Several studies have shown that unregulated expression or altered protein structure of DISC1 may predispose individuals to the development of schizophrenia, clinical depression, bipolar disorder, and other psychiatric conditions. The cellular functions that are disrupted by permutations in DISC1, which lead to the development of these disorders, have yet to be clearly defined and are the subject of current ongoing research.

In 1970, researchers from the University of Edinburgh performing cytogenetic research on a group of juvenile offenders in Scotland found an abnormal translocation in chromosome 1 of one of the boys, who also displayed characteristics of an affective psychological disorder.[4] After this initial observation, the boy’s family was studied and it was found that 34 out of 77 family members displayed the same translocation. According to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (or DSM-IV) criteria, sixteen of the 34 individuals identified as having the genetic mutation were diagnosed with psychiatric problems. In contrast, five of the 43 unaffected family members were identified to have psychological indispositions. The psychiatric illnesses observed in the family ranged from schizophrenia and major depression to bipolar disorder and adolescent conduct disorder (which the original research subject had).[5] After studying this large Scottish family for four generations, in 2000, this gene was given the name “DISC1”. The name was derived from the basis of the molecular nature of the mutation: the translocation directly disrupts the gene.[3]

Importance of genetic studies[edit]

The implication of genetics in psychiatric illnesses is not unique to schizophrenia, though the heritability of schizophrenia has been calculated as high as 80%.[6] The continued research of the family following the discovery of the translocation yielded statistical analysis of the probability of observing the simultaneous occurrence, or co-inheritance, of psychological afflictions and the translocation. This concept was measured quantitatively using the LOD, or logarithm of the odds value.[7] The higher the LOD value, the stronger the correlation between the presence of the translocation and given disease(s) is thought to be. The LOD for the chromosome 1 translocation and identification of schizophrenia alone in the Scottish family was found to be 3.6.[7]The LOD value of the translocation and a broader number of diagnoses (including schizophrenia, schizoaffective disorder, bipolar affective disorder, and recurrent major depression) was found to be 7.1.[7]

Besides large familial-based studies in which the pedigrees of various family members are examined, twin studies have also been a source of support for researchers in the investigation of DISC1.[6] In a meta-analysis of twin studies, twelve out of fourteen were found to support the fact that from a genetic perspective, schizophrenia is a complex trait that depends on both genetic and environmental factors.[6] Such findings have encouraged researchers to continue with both macro-analysis of the disorders afflicting individuals with the mutation, as well as explore the micro-level.


SCRIB, also known as Scribble, SCRIBL, or Scribbled homolog (Drosophila), is a scaffold protein which in humans is encoded by the SCRIB gene.[3][4] It was originally isolated in Drosophila melanogaster in a pathway (also known as the Scribble complex) with DLGAP5 (Discs large) and LLGL1 (Lethal giant larvae) as a tumor suppressor.[5] In humans, SCRIB is found as a membrane protein and is involved in cell migration, cell polarity, and cell proliferation in epithelial cells.[5][6] There is also strong evidence that SCRIB may play a role in cancer progression because of its strong homology to the Drosophila protein.

Subcellular and tissue distribution

SCRIB is found in the cell membrane most often as a peripheral membrane protein. The Scribble complex is localized at the basolateral membrane.[7] SCRIB is also found in cellular junctions such as adherens junctionsand tight junctions.[10] Specifically, it is located in the kidney, skeletal muscles, liver, lung, breast, intestine, placenta and epithelial cells.[11]

Clinical significance

The PDZ domain of SCRIB binds directly to the human papillomavirus E6 protein.[12] SCRIB is targeted for ubiquitination by a complex of E6 and UBE3A and E6 induces degradation of SCRIB.[12]

Role as a tumor suppressor

As mentioned above, SCRIB has been identified as a tumor suppressor along with DLGAP5 (Discs large) and LLGL1 (Lethal giant larvae).[5] Specifically, SCRIB deficient mutants have been shown to promote the activity of numerous oncogenes.[7] For example, SCRIB is known to inhibit breast cancer formation and the depletion of SCRIB promotes neoplastic growth by disrupting morphogenesis and inhibiting cell death through an association with Myc.[7][13] In human cells expressing oncogenic Ras or Raf, it was found the loss of SCRIB resulted in the invasion of the extracellular matrix by various cell types. This is believed to be a direct result of regulation of the MAP Kinase pathway by SCRIB.