A mouse model of 22q11.2 deletions: Molecular and behavioral signatures of Parkinson’s disease and schizophrenia

Abstract

22q11.2 deletions, a genetic risk for schizophrenia, could be susceptible to Parkinson’s disease through elevated expression of α-synuclein.

Lasting and Sex-Dependent Impact of Maternal Immune Activation on Molecular Pathways of the Amygdala

“…The WGCNA gene modules profiling changes between MIA groups in males uncovered enrichment of genes annotated to AD ( Table 9). This result is consistent with findings of common molecular mechanisms shared between SSD and AD (Prestia, 2011;Sumitomo et al, 2018). Likewise, the enrichment of ATP metabolic processes among the module of genes associated with MIA effects in males is in agreement with evidence that mitochondrial dysfunction associated with SSD (Prabakaran et al, 2004).…”

22q11.2 Deletion Syndrome–Associated Parkinson's Disease

“…Similar, but less profound, dopaminergic loss and comparable degrees of Lewy pathology were found in many other brain regions of these patients. Although several 22q11.2 deletion mouse models are available, only one study in a 22q11.2 deletion mouse model focused on neuropathological findings that may be relevant to 22q11.2DS‐associated PD . In this study in mice carrying a heterozygous deletion of mouse chromosome 16 ( Df1/ + mice) that is highly similar in gene content and size to the human 22q11.2 deletion, elevated expression of α‐synuclein proteins (1.3‐ to 1.8‐fold increase compared to wild‐type control mice) was found in the anterior cingulate cortex, dorsolateral part of caudate putamen, and SNpc at 3.5 and 8 months of age (roughly equivalent to the twenties and forties in humans, respectively).…”

“…Although several 22q11.2 deletion mouse models are available, 40 only one study in a 22q11.2 deletion mouse model focused on neuropathological findings that may be relevant to 22q11.2DS-associated PD. 41 In this study in mice carrying a heterozygous deletion of mouse chromosome 16 (Df1/ + mice) that is highly similar in gene content and size to the human 22q11.2 deletion, 42 elevated expression of α-synuclein proteins (1.3-to 1.8-fold increase compared to wild-type control mice) was found in the anterior cingulate cortex, dorsolateral part of caudate putamen, and SNpc at 3.5 and 8 months of age (roughly equivalent to the twenties and forties in humans, respectively). Homologues of individual genes within the 22q11.2 region may also be studied in other simple model organisms using knockdown or knockout models, some of which display motor abnormalities, for example, a Drosophila homologue of PRODH knockout (slgA).…”

BDNF controls cognitive processes related to neuropsychiatric manifestations via autophagic regulation of p62 and GABAA receptor trafficking

“…For instance, p62 protein levels typically increase with age, reflecting a gradual decrease in cellular autophagic activity (Vilchez et al, 2014), and elevated p62 levels or increase in p62 + inclusions are cardinal features of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases (Ferrer et al, 2011;Salminen et al, 2012). Furthermore, we recently reported upregulated expression of p62 proteins in cultured neurons isolated from subjects with schizophrenia and bipolar disorder (Sumitomo et al, 2018a), and in brains of a mouse model of schizophrenia (Sumitomo et al 2018b). Hence, controlling the dosage of p62 protein may provide a potential target for therapeutic intervention against symptoms shared across these disorders, such as cognitive impairment, through augmentation of inhibitory neurotransmission.…”