Recent schizophrenia research supports a model wherein aberrant brain changes in late-adolescence contribute to the onset and early progression of disease.1 To further examine this model, longitudinal studies of genetic high-risk subjects, including those in prodromal stage, have recently been conducted.2 Parallel studies evaluating patients with recent-onset schizophrenia are growing in number.3 Nonetheless, almost all these studies are limited to clinical and neuropsychological characterization, and to brain imaging. Therefore, the molecular mechanisms underlying these dynamic changes remain elusive. In order to address this fundamental question with better molecular understanding, we have examined the cerebrospinal fluid (CSF) from patients with recent-onset schizophrenia (within the first five years of disease) and have compared these samples to those from age-matched healthy controls and patients with chronic schizophrenia (five or more years of schizophrenia) (Supplementary Table 1). Building on the hypothesis that oxidative stress and associated neuroinflammatory response may play a role in this dynamic process,4 we measured the levels of 14 selected molecules (Supplementary Table 2). Here we report the novel finding of a dramatically reduced level of soluble superoxide dismutase-1 (SOD1) in CSF from patients with recent-onset schizophrenia in contrast to samples from age-matched healthy controls (Table 1, Supplementary Figure 1). Furthermore, the level of CSF soluble SOD1 from recent-onset patients is lower than that from patients with chronic schizophrenia. To our knowledge, this is the first report of decreased CSF SOD1 in recent-onset schizophrenia. We also highlight that while the sample size of patients with one year or less disease is small, the absolute concentrations of soluble SOD1 are most robustly decreased in this cohort. We speculate that the decrease in soluble SOD1 between patients with one year or less disease and age-matched healthy controls is limited in significance by the small sample size. Table 1 Comparison of CSF soluble SOD1 concentration between patients with recent-onset schizophrenia (less than five years disease) grouped by disease duration and age-matched healthy controls. While our reported observations require replication in a larger sample, this study implies two innovative conceptual contributions. First, the reduction of soluble SOD1 may directly underlie oxidative stress at the onset of schizophrenia through decreased availability of this important antioxidant enzyme. We further note that this decrease in CSF soluble SOD1 concentration could be a secondary effect of another pro-oxidative process. Nevertheless, this ultimate decrease in soluble SOD1 is likely to facilitate overall oxidative stress. Thus, we provide further evidence of the “oxidative stress hypothesis” in schizophrenia. Second, we note the possibility that a decrease in CSF soluble SOD1 may reflect an increase in “insoluble” SOD1. This is analogous to decreased Aβ1-42 in CSF from patients with Alzheimer’s disease reflecting insoluble Aβ1-42 and senile plaques.5 Likewise, SOD1 is amyloidogenic and can be associated with brain disorders, such as amyotrophic lateral sclerosis (ALS).6 We wish to recall that aggregate formation in Huntington’s disease and other brain disorders has been discovered only after specific probing of target molecules, such as Huntingtin detection using a specific antibody.7 Therefore, it is crucial to now explore insoluble SOD1 in autopsied brains or biopsied cells (e.g. induced neurons from fibroblasts, olfactory neurons) from patients with recent-onset schizophrenia, and such future studies may utilize antibodies against insoluble forms of SOD1.8 A role of misfolded protein in schizophrenia has also been suggested by studies stemming from genetic susceptibility factors. Korth and associates9 reported the recruitment of Dysbindin protein to cell-invasive DISC1 aggresomes, suggesting the important convergence of two promising genetic risk factors and the significance of protein insolubility in cases of schizophrenia. The levels of CSF soluble SOD1 are not significantly different between chronic cases and matched healthy controls (data not shown). The possible contrast in SOD1 between recent-onset schizophrenia and chronic cases may be addressed in follow-up studies with larger sample size. It is possible that transient downregulation around the onset of schizophrenia might play an important pathophysiological role. Of note, some studies suggest that neuroleptic medication might increase plasma or serum SOD levels,10 although levels between peripheral blood and CSF are not necessarily correlated. In this report with one exception, all patients were on medication at the time of CSF acquisition. In summary, we report diminished CSF soluble SOD1 in cases of recent-onset schizophrenia and discuss this observation as supporting the previously proposed role of “oxidative stress” in the pathophysiology and onset of this disease. Increased oxidative stress can lead to synaptic deterioration and interneuron deficits relevant to the pathophysiology of schizophrenia. Furthermore, this observation may also be an entry point for other working hypotheses, such as those of SOD1 protein misfolding and aberrant control of proteolysis, which prompt further investigation.
Read full abstract
Jan 1, 2013
Zafar Ahmad Malik + 2
Open Access
