Mutations in

␤-Amyloid (A␤) pathology is an essential pathogenic component in Alzheimer's disease (AD). However, the significance of A␤ pathology, including A␤ deposits/oligomers and glial reactions, to neurodegeneration is unclear. In particular, despite the A␤ neurotoxicity indicated by in vitro studies, mouse models with significant A␤ deposition lack robust and progressive loss of forebrain neurons. Such results have fueled the view that A␤ pathology is insufficient for neurodegeneration in vivo. In this study, because monoaminergic (MAergic) neurons show degenerative changes at early stages of AD, we examined whether the APPswe/PS1⌬E9 mouse model recapitulates progressive MAergic neurodegeneration occurring in AD cases. We show that the progression forebrain A␤ deposition in the APPswe/ PS1⌬E9 model is associated with progressive losses of the forebrain MAergic afferents. Significantly, axonal degeneration is associated with significant atrophy of cell bodies and eventually leads to robust loss (ϳ50%) of subcortical MAergic neurons. Degeneration of these neurons occurs without obvious local A␤ or tau pathology at the subcortical sites and precedes the onset of anxiety-associated behavior in the mice. Our results show that a transgenic mouse model of A␤ pathology develops progressive MAergic neurodegeneration occurring in AD cases.

The ubiquitin-proteasome system (UPS) mediates targeted protein degradation. Notably, the UPS determines levels of key checkpoint proteins controlling apoptosis and proliferation by controlling protein half-life. Herein, we show that ovarian carcinoma manifests an overstressed UPS by comparison with normal tissues by accumulation of ubiquitinated proteins despite elevated proteasome levels. Elevated levels of total ubiquitinated proteins and 19S and 20S proteasome subunits are evident in both low-grade and high-grade ovarian carcinoma tissues relative to benign ovarian tumors and in ovarian carcinoma cell lines relative to immortalized surface epithelium. We find that ovarian carcinoma cell lines exhibit greater sensitivity to apoptosis in response to proteasome inhibitors than immortalized ovarian surface epithelial cells. This sensitivity correlates with increased cellular proliferation rate and UPS stress rather than absolute proteasome levels. Proteasomal inhibition in vitro induces cell cycle arrest and the accumulation of p21 and p27 and triggers apoptosis via activation of caspase-3. Furthermore, treatment with the licensed proteasome inhibitor PS-341 slows the growth of ES-2 ovarian carcinoma xenograft in immunodeficient mice. In sum, elevated proliferation and metabolic rate resulting from malignant transformation of the epithelium stresses the UPS and renders ovarian carcinoma more sensitive to apoptosis in response to proteasomal inhibition. (Cancer Res 2006; 66(7): 3754-63)

Mutations in the genes coding for ␣-synuclein and parkin cause autosomal-dominant and autosomal-recessive forms of Parkinson's disease (PD), respectively. ␣-Synuclein is a major component of Lewy bodies, the proteinaceous cytoplasmic inclusions that are the pathological hallmark of idiopathic PD. Lewy bodies appear to be absent in cases of familial PD associated with mutated forms of parkin. Parkin is an ubiquitin E3 ligase, and it may be involved in the processing and/or degradation of ␣-synuclein, as well as in the formation of Lewy bodies. Here we report the behavioral, biochemical, and histochemical characterization of double-mutant mice overexpressing mutant human A53T ␣-synuclein on a parkin null background. We find that the absence of parkin does not have an impact on the onset and progression of the lethal phenotype induced by overexpression of human A53T ␣-synuclein. Furthermore, all major behavioral, biochemical, and morphological characteristics of A53T ␣-synuclein-overexpressing mice are not altered in parkin null ␣-synucleinoverexpressing double-mutant mice. Our results demonstrate that mutant ␣-synuclein induces neurodegeneration independent of parkin-mediated ubiquitin E3 ligase activity in nondopaminergic systems and suggest that PD caused by ␣-synuclein and parkin mutations may occur via independent mechanisms.

Biochemical and genetic abnormalities of a-synuclein (a-Syn) are implicated in the pathogenesis of Parkinson's disease (PD) and other a-synucleinopathies. The abnormal intraneuronal accumulations of a-Syn in Lewy bodies (LBs) and Lewy neurites (LNs) have implicated defects in axonal transport of a-Syn in the a-synucleinopathies. Using human (Hu) a-Syn transgenic (Tg) mice, we have examined whether familial PD (FPD)-linked mutations (A30P and A53T) alter axonal transport of Hua-Syn. Our studies using peripheral nerves show that Hua-Syn and Moa-Syn are almost exclusively transported in the slow component (SC) of axonal transport and that the FPD-linked a-Syn mutations do not have obvious effects on the axonal transport of a-Syn.Moreover, older pre-symptomatic A53T Hua-Syn Tg mice do not show gross alterations in the axonal transport of a-Syn and other proteins in the SC, indicating that the early stages of a-synucleinopathy in A53T a-Syn Tg mice are not associated with gross alterations in the slow axonal transport. However, the axonal transport of a-Syn slows significantly with aging. Because the rate of axonal transport affects the stability and accumulation of proteins in axons, age-dependent-slowing a-Syn is a likely contributor to axonal aggregation of a-Syn in a-synucleinopathy.