Autophagy has a key role in the pathophysiology of schizophrenia

Abstract

Autophagy is a process preserving the balance between synthesis, degradation and recycling of cellular components and is therefore essential for neuronal survival and function. Several key proteins govern the autophagy pathway including beclin1 and microtubule associated protein 1 light chain 3 (LC3). Here, we show a brain-specific reduction in beclin1 expression in postmortem hippocampus of schizophrenia patients, not detected in peripheral lymphocytes. This is in contrast with activity-dependent neuroprotective protein (ADNP) and ADNP2, which we have previously found to be deregulated in postmortem hippocampal samples from schizophrenia patients, but that now showed a significantly increased expression in lymphocytes from related patients, similar to increases in the anti-apoptotic, beclin1-interacting, Bcl2. The increase in ADNP was associated with the initial stages of the disease, possibly reflecting a compensatory effect. The increase in ADNP2 might be a consequence of neuroleptic treatment, as seen in rats subjected to clozapine treatment. ADNP haploinsufficiency in mice, which results in age-related neuronal death, cognitive and social dysfunction, exhibited reduced hippocampal beclin1 and increased Bcl2 expression (mimicking schizophrenia and normal human aging). At the protein level, ADNP co-immunoprecipitated with LC3B suggesting a direct association with the autophagy process and paving the path to novel targets for drug design.

The Compassionate Side of Neuroscience: Tony Sermone’s Undiagnosed Genetic Journey—ADNP Mutation

“…Using biochemical and cell biology techniques, we showed multiple crucial interactions for ADNP, including the chromatin remodeling complex SWI/SNF , the RNA splicing machinery (Schirer et al 2014), protein translation (Malishkevich et al 2015), as well as the microtubule (Oz et al 2014) and autophagy systems (Merenlender-Wagner et al 2015). However, no good science can exist without listening and watching the society needs and hearing out the parents and wonderful caretakers of the ADNP children, which follows herein (Sandra Bedrosian Sermone, Our Undiagnosed Genetic Journey-ADNP mutation, 2015).…”

“…Taking advantage of mouse genetics, we have shown that ADNP is crucial for brain formation (Pinhasov et al 2003) and learning and memory (Vulih-Shultzman et al 2007), in a sex-dependent manner (Malishkevich et al 2015;Kleiman et al 2015). Using biochemical and cell biology techniques, we showed multiple crucial interactions for ADNP, including the chromatin remodeling complex SWI/SNF , the RNA splicing machinery (Schirer et al 2014), protein translation (Malishkevich et al 2015), as well as the microtubule (Oz et al 2014) and autophagy systems (Merenlender-Wagner et al 2015).…”

Specific protein biomarker patterns for Alzheimer’s disease: improved diagnostics in progress

“…In this respect, it is interesting to add that ADNP regulates cathepsin expression [31]. ADNP was further associated with autophagy [32]. Developing an algorithm that will take into account variations and relationships among the potential biomarkers listed above and beyond will bring us closer to precision medicine.…”

Study of NAP adsorption and assembly on the surface of HOPG

“…It is a peptide snippet from the activity-dependent neuroprotective protein (ADNP), [1], a protein essential for brain formation [20,24] recently found to be mutated in autism [10], deregulated in schizophrenia [5,21] and in patients with Alzheimer's disease [29]. In this respect, multiple preclinical evaluations, as well as clinical trials with NAP (davunetide) showed efficacy of the peptide [18,19].…”