Measurement of proteasomal dysfunction in cell models of dopaminergic degeneration.

Parkinson's disease (PD) is the second most common neurodegenerative diseases, which occurs in both inheritable and sporadic forms. The interplay of the genetic mutations and environmental exposure to disease risk factors contributes to the pathogenic events leading to the demise of dopaminergic neurons in PD. Proteasome is one of the major proteolytic machinery responsible for degrading unwanted and damaged intracellular proteins.

Sunday Driver/JIP3 binds kinesin heavy chain directly and enhances its motility.

Neuronal development, function and repair critically depend on axonal transport of vesicles and protein complexes, which is mediated in part by the molecular motor kinesin-1. Adaptor proteins recruit kinesin-1 to vesicles via direct association with kinesin heavy chain (KHC), the force-generating component, or via the accessory light chain (KLC). Binding of adaptors to the motor is believed to engage the motor for microtubule-based transport.

Neuroproteomics approaches to decipher neuronal regeneration and degeneration.

Given the complexity of brain and nerve tissues, systematic approaches are essential to understand normal physiological conditions and functional alterations in neurological diseases. Mass spectrometry-based proteomics is increasingly used in neurosciences to determine both basic and clinical differential protein expression, protein-protein interactions, and post-translational modifications. Proteomics approaches are especially useful to understand the mechanisms of nerve regeneration and degeneration because changes in axons following injury or in disease states often occur without the contribution of transcriptional events in the cell body.

Mitochondrial accumulation of polyubiquitinated proteins and differential regulation of apoptosis by polyubiquitination sites Lys-48 and -63.

Proteins tagged with lysine (Lys, K) 48 polyubiquitins chains are destined for degradation by the 26S proteasomal system. Impairment of the ubiquitin proteasome system (UPS) function culminates in the accumulation of polyubiquitinated proteins in many neurodegenerative conditions including Parkinson's disease (PD). Nevertheless, the cellular mechanisms underlying cell death induced by an impaired UPS are still not clear.

Apoptosis induced by baicalin involving up-regulation of P53 and bax in MCF-7 cells.

Anticancer effect of baicalin (1) has been well documented. However, the molecular mechanisms underlying the cytotoxicity of baicalin in cancer cells remain unclear. In the present study, we examined the potential roles of p53, bax, and bcl-2 in baicalin-triggered apoptosis in MCF-7 cells, a cell line derived from human breast cancer.

Proteasome inhibitor-induced apoptosis is mediated by positive feedback amplification of PKCdelta proteolytic activation and mitochondrial translocation.

Emerging evidence implicates impaired protein degradation by the ubiquitin proteasome system (UPS) in Parkinson's disease; however cellular mechanisms underlying dopaminergic degeneration during proteasomal dysfunction are yet to be characterized. In the present study, we identified that the novel PKC isoform PKCdelta plays a central role in mediating apoptotic cell death following UPS dysfunction in dopaminergic neuronal cells. Inhibition of proteasome function by MG-132 in dopaminergic neuronal cell model (N27 cells) rapidly depolarized mitochondria independent of ROS generation to activate the apoptotic cascade involving cytochrome c release, and caspase-9 and caspase-3 activation.

Environmental neurotoxic chemicals-induced ubiquitin proteasome system dysfunction in the pathogenesis and progression of Parkinson's disease.

Proteolytic degradation of unwanted proteins by the ubiquitin-proteasome system (UPS) is critical for normal maintenance of various cellular functions. Parkinson's disease (PD), one of the most prevalent neurodegenerative disorders, is characterized by prominent and irreversible nigral dopaminergic neuronal loss and intracellular protein aggregations. Epidemiological studies imply both environmental neurotoxins and genetic predisposition as potential risk factors for PD, though mechanisms underlying selective dopaminergic degeneration remain unclear.

Proteasome inhibitor MG-132 induces dopaminergic degeneration in cell culture and animal models.

Impairment in ubiquitin-proteasome system (UPS) has recently been implicated in Parkinson's disease, as demonstrated by reduced proteasomal activities, protein aggregation and mutation of several genes associated with UPS. However, experimental studies with proteasome inhibitors failed to yield consensus regarding the effect of proteasome inhibition on dopaminergic degeneration. In this study, we systematically examined the effect of the proteasome inhibitor MG-132 on dopaminergic degeneration in cell culture and animal models of Parkinson's disease.

Dieldrin induces ubiquitin-proteasome dysfunction in alpha-synuclein overexpressing dopaminergic neuronal cells and enhances susceptibility to apoptotic cell death.

Exposure to pesticides is implicated in the etiopathogenesis of Parkinson's disease (PD). The organochlorine pesticide dieldrin is one of the environmental chemicals potentially linked to PD. Because recent evidence indicates that abnormal accumulation and aggregation of alpha-synuclein and ubiquitin-proteasome system dysfunction can contribute to the degenerative processes of PD, in the present study we examined whether the environmental pesticide dieldrin impairs proteasomal function and subsequently promotes apoptotic cell death in rat mesencephalic dopaminergic neuronal cells overexpressing human alpha-synuclein.