Alteration of dynein function affects α-synuclein degradation via the autophagosome-lysosome pathway.

Growing evidence suggests that dynein dysfunction may be implicated in the pathogenesis of neurodegeneration. It plays a central role in aggresome formation, the delivery of autophagosome to lysosome for fusion and degradation, which is a pro-survival mechanism essential for the bulk degradation of misfolded proteins and damaged organells. Previous studies reported that dynein dysfuntion was associated with aberrant aggregation of α-synuclein, which is a major component of inclusion bodies in Parkinson's disease (PD). However, it remains unclear what roles dynein plays in α-synuclein degradation. Our study demonstrated a decrease of dynein expression in neurotoxin-induced PD models in vitro and in vivo, accompanied by an increase of α-synuclein protein level. Dynein down-regulation induced by siRNA resulted in a prolonged half-life of α-synuclein and its over-accumulation in A53T overexpressing PC12 cells. Dynein knockdown also prompted the increase of microtubule-associated protein 1 light chain 3 (LC3-II) and sequestosome 1 (SQSTM1, p62) expression, and the accumulation of autophagic vacuoles. Moreover, dynein suppression impaired the autophagosome fusion with lysosome. In summary, our findings indicate that dynein is critical for the clearance of aberrant α-synuclein via autophagosome-lysosome pathway.

Comparative study on the influence of final use structure on carbon emissions in the Beijing-Tianjin-Hebei region.

The Beijing-Tianjin-Hebei region's rapid economic development has led to a dramatic increase in its CO2 emissions, which is closely related to various regions' consumption habits and structures. In this paper, the decomposition analysis method based on input and output (IO-SDA) was applied to decompose the CO2 emissions change of the Beijing-Tianjin-Hebei region from 1997 to 2012 into five driving factors: population, carbon emission efficiency, production structure, final use structure and per capita regional GDP, and then the final use structure factor was further analyzed. The results show that: (1) the population and per capita regional GDP promote the CO2 emissions of all regions; Carbon emission efficiency is the biggest offsetting factor; The effect of final use structure changes on the growth of CO2 emissions in Beijing and Hebei remains unchanged. The effect on Tianjin was from 0.7Mt offset to 0.8Mt promotion. (2) Urban household consumption is the most important factor offsetting CO2 emissions in Beijing. Investment and export are the most important final use types for promoting the growth of CO2 emissions in Tianjin and Hebei, with the contribution of 95.78% and 88.09%, respectively. (3) From the sectoral perspective: The construction sector has the greatest impact on the total capital formation of the three regions. In terms of exports, Beijing's tertiary industry has the largest offsetting effect, while Tianjin and Hebei mainly rely on the promotion of metal smelting and other manufacturing industries. Finally, some policy implications for low carbonization are proposed in the Beijing-Tianjin-Hebei region.

Exploring the changes and driving forces of water footprints in China from 2002 to 2012: A perspective of final demand.

Due to economic development and population growth, the water shortage in China has gradually become increasingly severe. In this paper, by developing an environmentally expanded input-output (IO) model, water footprint in China during 2002-2012 is calculated from the perspective of final demand. Furthermore, a structural decomposition analysis (SDA) model is used to study the driving factors of the water footprint of rural and urban household consumption, gross fixed capital formation and exports. The findings indicate that: 1) the water footprint driven by final demand in China increased by 18.3% during 2002-2012, reaching 617.68 billion m3 in 2012, of which urban household consumption accounts for the highest proportion. 2) Of the different sectors, agricultural commodities have the highest water footprint, accounting for 35% of national water footprint in 2012. 3) In terms of the driving factors, water efficiency inhibits the increase of water footprint regardless of final demand types, while GDP per capita makes a great contribution to its rise. 4) As for rural household consumption, the most important driving factor is the inhibition effects of consumption pattern in water footprint. For urban household consumption, the water footprint is inhibited by consumption pattern but promoted by production structure during 2002-2010. However, it is no longer the case during 2010-2012 that consumption pattern becomes a promoting factor, with production structure being inhibiting one. 5) Regarding gross fixed capital formation, its water footprint increase driven by consumption pattern is only 12.4 billion m3 during 2007-2010. As for exports, consumption pattern causes the decline of water footprint after 2005 and the overall water footprint of exports declines during 2007-2012. Finally, this paper provides policy implications with respect to the promotion of China's water footprint conservation.

TNF compromises lysosome acidification and reduces α-synuclein degradation via autophagy in dopaminergic cells.

Tumor necrosis factor-α (TNF) is increasingly implicated as a critical pro-inflammatory cytokine involved in chronic inflammation and neurodegeneration of Parkinson's disease (PD). However, the cellular and molecular events that lead to dopaminergic neuron degeneration are not fully understood. In this study, we demonstrated that microglia-released and recombinant TNF disrupted α-synuclein (α-SYN) degradation and caused its accumulation in PC12 cells and midbrain neurons. At subtoxic doses, recombinant TNF was found to increase the number of LC3 puncta dots and LC3II protein level, associated with the increases of P62 protein level. Inhibition of lysosomal degradation with Bafilomycin A1 pretreatment abrogated the TNF-induced elevation in LC3II protein level whereas autophagy inhibitor 3-methyladenine did not affect it. Moreover, TNF led to a marked increase in the number of yellow LC3 dots with a marginal elevation in red-only dots in RFP-GFP-tandem fluorescent LC3 (tf-LC3) transfected PC12 cells, implying the impairment in autophagic flux. Furthermore, TNF treatment reduced lysosomal acidification, as LysoTracker Red fluorescence and LysoSensor fluorescence shift from blue to yellow was markedly decreased in TNF-treated PC12 cells. Co-treatment with mammalian target of rapamycin kinase complex 1 (mTORC1) inhibitor PP242, which activated transcription factor EB (TFEB) signaling and lysosome biogenesis, partially rescued the accumulation of α-SYN in PC12 cells and midbrain neurons. Taken together, our results demonstrated that at subtoxic levels, TNF was able to impair autophagic flux and result in α-SYN accumulation by compromising lysosomal acidification in dopaminergic cells. This may represent a novel mechanism for TNF-induced dopaminergic neuron degeneration in PD.

A pivotal role of FOS-mediated BECN1/Beclin 1 upregulation in dopamine D2 and D3 receptor agonist-induced autophagy activation.

Autophagy dysfunction is implicated in the pathogenesis of Parkinson disease (PD). BECN1/Beclin 1 acts as a critical regulator of autophagy and other cellular processes; yet, little is known about the function and regulation of BECN1 in PD. In this study, we report that dopamine D2 and D3 receptor (DRD2 and DRD3) activation by pramipexole and quinpirole could enhance BECN1 transcription and promote autophagy activation in several cell lines, including PC12, MES23.5 and differentiated SH-SY5Y cells, and also in tyrosine hydroxylase positive primary midbrain neurons. Moreover, we identified a novel FOS (FBJ murine osteosarcoma viral oncogene homolog) binding sequence (5'-TGCCTCA-3') in the rat and human Becn1/BECN1 promoter and uncovered an essential role of FOS binding in the enhancement of Becn1 transcription in PC12 cells in response to the dopamine agonist(s). In addition, we demonstrated a critical role of intracellular Ca2+ elevation, followed by the enhanced phosphorylation of CAMK4 (calcium/calmodulin-dependent protein kinase IV) and CREB (cAMP responsive element binding protein) in the increases of FOS expression and autophagy activity. More importantly, pramipexole treatment ameliorated the SNCA/α-synuclein accumulation in rotenone-treated PC12 cells that overexpress wild-type or A53T mutant SNCA by promoting autophagy flux. This effect was also demonstrated in the substantia nigra and the striatum of SNCAA53T transgenic mice. The inhibition of SNCA accumulation by pramipexole was attenuated by cotreatment with the DRD2 and DRD3 antagonists and Becn1 siRNAs. Thus, our findings suggest that DRD2 and DRD3 agonist(s) may induce autophagy activation via a BECN1-dependent pathway and have the potential to reduce SNCA accumulation in PD.

Autophagic impairment contributes to systemic inflammation-induced dopaminergic neuron loss in the midbrain.

BACKGROUND: Neuroinflammation plays an important role in the pathogenesis of Parkinson's disease (PD), inducing and accelerating dopaminergic (DA) neuron loss. Autophagy, a critical mechanism for clearing misfolded or aggregated proteins such as α-synuclein (α-SYN), may affect DA neuron survival in the midbrain. However, whether autophagy contributes to neuroinflammation-induced toxicity in DA neurons remains unknown. RESULTS: Intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) into young (3-month-old) and aged (16-month-old) male C57BL/6J mice was observed to cause persistent neuroinflammation that was associated with a delayed and progressive loss of DA neurons and accumulation of α-SYN in the midbrain. The autophagic substrate-p62 (SQSTM1) persistently increased, whereas LC3-II and HDAC6 exhibited early increases followed by a decline. In vitro studies further demonstrated that TNF-α induced cell death in PC12 cells. Moreover, a sublethal dose of TNF-α (50 ng/ml) increased the expression of LC3-II, p62, and α-SYN, implying that TNF-α triggered autophagic impairment in cells. CONCLUSION: Neuroinflammation may cause autophagic impairment, which could in turn result in DA neuron degeneration in midbrain.