Abstractα-Synuclein is likely to play a key role in the development of Parkinson's disease as well as other synucleinopathies. In animal models, overexpression of full-length or carboxy-terminally truncated α-synuclein has been shown to produce pathology. Although the proteosome and lysosome have been proposed to play a role in the degradation of α-synuclein, the enzyme(s) involved in α-synuclein clearance and generation of its carboxy-terminally truncated species have not been identified. In this study, the role of cathepsin D and calpain I in these processes was analyzed. In vitro experiments, using either recombinant or endogenous α-synuclein as substrates and purified cathepsin D or lysosomes, demonstrated that cathepsin D degraded α-synuclein very efficiently, and that limited proteolysis resulted in the generation of carboxy-terminally truncated species. Purified calpain I also cleaved α-synuclein, but carboxy-terminally truncated species were not the main cleavage products, and calpain I activity present in cellular lysates was not able to degrade the protein. Knockdown of cathepsin D in cells overexpressing wild-type α-synuclein increased total α-synuclein levels by 28% and lysosomal α-synuclein by 2-fold. In in vitro experiments, pepstatin A completely blocked the degradation of α-synuclein in purified lysosomes. Furthermore, lysosomes isolated from cathepsin D knockdown cells showed a marked reduction in α-synuclein degrading activity, indicating that cathepsin D is the main lysosomal enzyme involved in α-synuclein degradation. Our findings suggest that upregulation of cathepsin D could be an additional therapeutic strategy to lessen α-synuclein burden in synucleinopathies.Parkinson's disease (PD) 1 , dementia with Lewy bodies, Lewy body variant of Alzheimer's disease, and multiple system atrophy are among diseases collectively known as synucleinopathies [1][2][3]. This group of disorders is characterized by the presence of brain inclusions composed mainly of filamentous aggregates of α-synuclein (α-syn).The role of α-syn in synucleinopathies is supported by: 1) the identification of α-syn as the main component of Lewy bodies and Lewy neurites, two characteristic pathological inclusions found in all sporadic and familial cases of PD, and in other neurodegenerative diseases [1][2][3]; and 2) the discovery of point mutations in the α-syn gene in familial forms of autosomal PD [4,5]. A direct link between α-syn and PD is further supported by the discovery that multiplications of the wild-type sequence of the α-syn gene cause autosomal-dominant

In Alzheimer's disease (AD), the accumulation and deposition of amyloid-␤ (A␤) peptides in the brain is a central event. A␤ is cleaved from amyloid precursor protein (APP) by ␤-secretase and ␥-secretase mainly in neurons. Although mutations in APP, PS1, or PS2 cause early-onset familial AD, ABCA7 encoding ATP-binding cassette transporter A7 is one of the susceptibility genes for late-onset AD (LOAD), in which its loss-of-function variants increase the disease risk. ABCA7 is homologous to a major lipid transporter ABCA1 and is highly expressed in neurons and microglia in the brain. Here, we show that ABCA7 deficiency altered brain lipid profile and impaired memory in ABCA7 knock-out (Abca7 Ϫ / Ϫ ) mice. When bred to amyloid model APP/PS1 mice, plaque burden was exacerbated by ABCA7 deficit. In vivo microdialysis studies indicated that the clearance rate of A␤ was unaltered. Interestingly, ABCA7 deletion facilitated the processing of APP to A␤ by increasing the levels of ␤-site APP cleaving enzyme 1 (BACE1) and sterol regulatory element-binding protein 2 (SREBP2) in primary neurons and mouse brains. Knock-down of ABCA7 expression in neurons caused endoplasmic reticulum stress highlighted by increased level of protein kinase R-like endoplasmic reticulum kinase (PERK) and increased phosphorylation of eukaryotic initiation factor 2␣ (eIF2␣). In the brains of APP/PS1;Abca7 Ϫ / Ϫ mice, the level of phosphorylated extracellular regulated kinase (ERK) was also significantly elevated. Together, our results reveal novel pathways underlying the association of ABCA7 dysfunction and LOAD pathogenesis.

Our findings suggest that MMP-9 contributes to the pathogenesis of brain extravasation and edema in FHF. The necrotic liver is the source of MMP-9 in FHF. Inhibition of MMP-9 may protect against the development of brain edema in FHF.