Lysosomal stress drives the release of pathogenic α-synuclein from macrophage lineage cells via the LRRK2-Rab10 pathway.

α-Synuclein and LRRK2 are associated with both familial and sporadic Parkinson's disease (PD), although the mechanistic link between these two proteins has remained elusive. Treating cells with lysosomotropic drugs causes the recruitment of LRRK2 and its substrate Rab10 onto overloaded lysosomes and induces extracellular release of lysosomal contents. Here we show that lysosomal overload elicits the release of insoluble α-synuclein from macrophages and microglia loaded with α-synuclein fibrils. This release occurred specifically in macrophage lineage cells, was dependent on the LRRK2-Rab10 pathway and involved exosomes. Also, the uptake of α-synuclein fibrils enhanced the LRRK2 phosphorylation of Rab10, which was accompanied by an increased recruitment of LRRK2 and Rab10 onto lysosomal surface. Our data collectively suggest that α-synuclein fibrils taken up in lysosomes activate the LRRK2-Rab10 pathway, which in turn upregulates the extracellular release of α-synuclein aggregates, leading to a vicious cycle that could enhance α-synuclein propagation in PD pathology.

Targeting of Lysosomal Pathway Genes for Parkinson's Disease Modification: Insights From Cellular and Animal Models.

Previous genetic studies on hereditary Parkinson's disease (PD) have identified a set of pathogenic gene mutations that have strong impacts on the pathogenicity of PD. In addition, genome-wide association studies (GWAS) targeted to sporadic PD have nominated an increasing number of genetic variants that influence PD susceptibility. Although the clinical and pathological characteristics in hereditary PD are not identical to those in sporadic PD, α-synuclein, and LRRK2 are definitely associated with both types of PD, with LRRK2 mutations being the most frequent cause of autosomal-dominant PD. On the other hand, a significant portion of risk genes identified from GWAS have been associated with lysosomal functions, pointing to a critical role of lysosomes in PD pathogenesis. Experimental studies have suggested that the maintenance or upregulation of lysosomal activity may protect against neuronal dysfunction or degeneration. Here we focus on the roles of representative PD gene products that are implicated in lysosomal pathway, namely LRRK2, VPS35, ATP13A2, and glucocerebrosidase, and provide an overview of their disease-associated functions as well as their cooperative actions in the pathogenesis of PD, based on the evidence from cellular and animal models. We also discuss future perspectives of targeting lysosomal activation as a possible strategy to treat neurodegeneration.

Synthesis of eudistomin D analogues and its effects on adenosine receptors.

Six analogues (1-6) of eudistomin D, a beta-carboline alkaloid from a marine tunicate Eudistoma olivaceum, were synthesized, and their affinity and selectivity for adenosine receptors A(1), A(2A), and A(3) were examined. All the synthetic compounds 1-6 did not show affinity to the adenosine A(1) receptor. Delta-carboline 3 exhibited the most potent affinity to the adenosine receptor A(3) among compounds 1-6. Delta-carbolines 3 and 4 showed better affinity than the corresponding beta-carbolines 1 and 2, respectively, while N-methylation (2, 4, and 6, respectively) of the pyrrole ring in 1, 3, and 5 resulted in the reduced affinity to the adenosine A(3) receptor. On the other hand, an eudistomin D derivative, BED, exhibited modest affinity to all the receptors A(1), A(2A), and A(3) but no selectivity.

Medial frontal cortex perfusion abnormalities as evaluated by positron emission tomography in women with climacteric symptoms.

OBJECTIVE: To identify functional changes in the brains of women with climacteric symptoms. Images of regional cerebral blood flow (rCBF) were compared statistically between women with and women without symptoms to identify changes in rCBF. Results may provide a better understanding of the neural basis of the symptoms, which are divided into three symptom clusters: vasomotor, psychological, and somatic. DESIGN: The study participants consisted of 12 women with moderate to severe climacteric symptoms (age 47.5 +/- 5.9 years, mean +/- SD) and 7 women with no symptoms (control group; age 49.6 +/- 4.2 years, mean +/- SD). The study participants were patients at a menopause clinic, and the latter were healthy volunteer nurses and hospital staff. Climacteric symptoms were evaluated by an assessment of the severity of 17 symptoms immediately before positron emission tomography examination of rCBF. The symptoms had been used previously to generate the Kupperman Kohnenki Shogai Index, a modified Kupperman Menopausal Index adapted to Japanese women. rCBF was measured by positron emission tomography with the CO2 dynamic inhalation method. RESULTS: Reductions in relative rCBF in the patient group were observed in the bilateral rectal gyrus and in the left subcallosal gyrus on a voxel-by-voxel basis as compared with the control group. CONCLUSIONS: The present study revealed reductions in relative rCBF of the prefrontal cortex of Japanese women with moderate to severe climacteric symptoms. This area is close to that previously addressed in studies of familial bipolar depression and familial unipolar depression, although our participants did not satisfy criteria for depression. This reduction of rCBF may be related to the three climacteric symptom clusters, but further studies are needed for evaluation of its significance. Our results should stimulate investigations into the positron emission tomography rCBF change of these women as to the integration of multiple entities in climacteric symptoms.