Cathepsin D and apoptosis related proteins are elevated in the brain of autistic subjects

Sheikh, Ashfaq M.; Li, X.; Wen, Gen; Tauqeer, Zujaja; Brown, W. Ted; Malik, Mazhar N.

doi:10.1016/j.neuroscience.2009.10.035

Cited by 77 publications

(67 citation statements)

References 43 publications

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“…This finding was recently confirmed utilizing expression arrays and expression of the proapototic proteins caspase-3 and cathepsin D were significantly increased in autistic brain [Sheikh, 2010]. These findings suggest that increased apoptosis may contribute to the pathogenesis of autism.…”

Section: Intrinsic and Extrinsic Apoptosis Pathways And Autismsupporting

confidence: 54%

Autism and mitochondrial disease

Haas

2010

Dev Disabil Res Revs

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Autism spectrum disorder (ASD) as defined by the revised Diagnostic and Statistical Manual of Mental Disorders: DSM IVTR criteria (American Psychiatric Association [2000] Washington, DC: American Psychiatric Publishing) as impairment before the age of 3 in language development and socialization with the development of repetitive behaviors, appears to be increased in incidence and prevalence. Similarly, mitochondrial disorders are increasingly recognized. Although overlap between these disorders is to be expected, accumulating clinical, genetic, and biochemical evidence suggests that mitochondrial dysfunction in ASD is more commonly seen than expected. Some patients with ASD phenotypes clearly have genetic-based primary mitochondrial disease. This review will examine the data linking autism and mitochondria.

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Section: Intrinsic and Extrinsic Apoptosis Pathways And Autismsupporting

confidence: 54%

Autism and mitochondrial disease

Haas

2010

Dev Disabil Res Revs

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“…47,48 Previously, we found that the apoptosis-related proteins Bcl-2, p53, and cathepsin D are altered in both the brain and the lymphoblasts of autistic subjects. 4,32,49 The pathogenesis of autism may involve enhanced apoptosis in the brain and lymphoblasts. It is possible that the down-regulation of FAK-Src activities may contribute to an alteration of apoptosisrelated proteins in autism.…”

Section: Discussionmentioning

confidence: 99%

“…Susceptibility to autism is clearly attributable to the interplay of genetic and environmental factors, [1][2][3][4][5][6][7][8][9][10] but the etiology of this disorder is unknown and no biomarkers have yet been proved characteristic of autism. Recent research 11 is beginning to depict three major pathways as being potentially involved in the pathogenesis of autism (ie, reduced cell migration, excitatory-inhibitory imbalance, and abnormal synaptogenesis).…”

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confidence: 99%

Abnormal Cell Properties and Down-Regulated FAK-Src Complex Signaling in B Lymphoblasts of Autistic Subjects

Wei

Malik

Sheikh

et al. 2011

The American Journal of Pathology

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Recent studies suggest that one of the major pathways to the pathogenesis of autism is reduced cell migration. Focal adhesion kinase (FAK) has an important role in neural migration, dendritic morphological characteristics, axonal branching, and synapse formation. The FAK-Src complex, activated by upstream reelin and integrin ␤1, can initiate a cascade of phosphorylation events to trigger multiple intracellular pathways, including mitogen-activated protein kinaseextracellular signal-regulated kinase and phosphatidylinositol 3-kinase-Akt signaling. In this study, by using B lymphoblasts as a model, we tested whether integrin ␤1 and FAK-Src signaling are abnormally regulated in autism and whether abnormal FAK-Src signaling leads to defects in B-lymphoblast adhesion, migration, proliferation, and IgG production. To our knowledge, for the first time, we show that protein expression levels of both integrin ␤1 and FAK are significantly decreased in autistic lymphoblasts and that Src protein expression and the phosphorylation of an active site (Y416) are also significantly decreased. We also found that lymphoblasts from autistic subjects exhibit significantly decreased migration, increased adhesion properties, and an impaired capacity for IgG production. The overexpression of FAK in autistic lymphoblasts countered the adhesion and migration defects. In addition, we demonstrate that FAK mediates its effect through the activation of Src, phosphatidylinositol 3-kinase-Akt, and mitogen-activated protein kinase signaling cascades and that paxillin is also likely involved in the regulation of adhesion and migration in autistic lymphoblasts. Autism is a severe neurodevelopmental disorder characterized by problems in communication, social skills, and repetitive behavior. Susceptibility to autism is clearly attributable to the interplay of genetic and environmental factors, 1-10 but the etiology of this disorder is unknown and no biomarkers have yet been proved characteristic of autism. Recent research 11 is beginning to depict three major pathways as being potentially involved in the pathogenesis of autism (ie, reduced cell migration, excitatory-inhibitory imbalance, and abnormal synaptogenesis). The reelin protein encoded by the RELN gene plays a pivotal role in neuronal cell migration and the prenatal development of neural connections.12 Reelin has coexpressed with HAR1F, which is a novel RNA gene expressed specifically in Cajal-Retzius neurons in the developing human neocortex from gestational week 7 to 19 (a crucial period for cortical neuron specification and migration). 13 Linkage between RELN and autism is a replicated genetic finding in autism research, and reelin has been reduced in the serum and brain specimens of autistic subjects.14,15 Reelin can act through ␣3␤1 integrins and exert proteolytic activity on extracellular matrix (ECM) proteins, which are crucial for neuronal migration. 16 Most recently, emerging evidence 17 indicates that synaptic cell adhesion pathways are disrupted in some

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“…A number of studies have demonstrated that cathepsin D expression is decreased in Alzheimer's disease fibroblasts and cathepsin D activity protects against development of type AA amyloid fibrils [10,12]. Most recently, our laboratory also found that cathepsin D and apoptosis related proteins are elevated in the brain of autistic subjects, which suggest that the up-regulation of the cathepsin D could be associated with autism [11]. To facilitate the functional studies of cathepsin D related to autism and Alzheimer's disease, we report here that we purified and characterized cathepsin D from calf brain cytosol.…”

Section: Introductionmentioning

confidence: 78%

“…A number of studies have also shown that procathepsin D initiates the secretion of inflammatory cytokines, including IL-4, IL-8, IL-10 and IL-13 [8]. In addition, cathepsin D has been shown to be possibly involved in the pathogenesis of Alzheimer disease and autism [9][10][11]. A number of studies have demonstrated that cathepsin D expression is decreased in Alzheimer's disease fibroblasts and cathepsin D activity protects against development of type AA amyloid fibrils [10,12].…”

Section: Introductionmentioning

confidence: 99%

A Novel Approach for Characterization of Cathepsin D Protease and Its Effect on Tau and β-Amyloid Proteins

et al. 2011

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Cathepsin D is the lysosomal protease abundantly expressed in the brain. It plays an important role in the regulation of cellular apoptosis. In addition, cathepsin D has been shown to be involved in the pathogenesis of Alzheimer disease and autism. In this study, we developed a novel approach for the preparation of highly purified cathepsin D from the calf brain. This high grade purification is achieved by using DEAE-Sephacel Chromatography before the final step of applying to the Pepstatin-Sepharose 4B column. The properties of cathepsin D have also been studied. We show that cathepsin D cleaves both tau and β-amyloid precursor protein (APP). Both tau and APP are involved in the pathogenesis of Alzheimer's disease. Our findings strongly suggest a link between the lysosomal dysfunction of cathepsin D and the etiology of Alzheimer's disease. Our findings also indicate that cathepsin D could be a new approach to treating Alzheimer's disease.

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Cathepsin D and apoptosis related proteins are elevated in the brain of autistic subjects

Cited by 77 publications

References 43 publications

Autism and mitochondrial disease

Autism and mitochondrial disease

Abnormal Cell Properties and Down-Regulated FAK-Src Complex Signaling in B Lymphoblasts of Autistic Subjects

A Novel Approach for Characterization of Cathepsin D Protease and Its Effect on Tau and β-Amyloid Proteins

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