Reported by Benjamin Wolozin, Natalie Golts and Peter Choi, Loyola University Medical Center
The meeting in New Orleans demonstrated that the biology of α-synuclein and parkin are progressing at a rapid pace. Aggregation of α-synuclein is thought to play a pivotal role in the pathophysiology of Lewy body disease. Several studies presented advances in our understanding of the biology of α-synuclein aggregation. Ueda and colleagues (13.1) showed that α-synuclein binds tubulin and that tubulin fibrils act as nidus points that stimulate aggregation of α-synuclein. This is particularly interesting because dystrophic neuritis in Lewy body diseases are known to accumulate α-synuclein, and the ability of tubulin to serve as a nidus for α-synuclein aggregation provides a mechanistic underpinning for this phenomenon.
Golts, Wolozin and colleagues (13.5) looked at binding of metals to α-synuclein. They showed that iron promotes α-synuclein aggregation and magnesium inhibits aggregation. As with the work on tubulin, this work might shed light on mechanisms of α-synuclein aggregation in Lewy body diseases because brains of patients with Parkinson’s disease have increased iron and decreased magnesium, both of which would tend to promote α-synuclein aggregation.
Murray, Trojanowski, Lee and colleagues (84.10) also looked at the biochemistry of α-synuclein aggregation. They suggest that amino acids 71-82 are critical for α-synuclein aggregation. They also examined pharmacological agents that might inhibit aggregation of α-synuclein. Congo-red and thioflavine are known to bind to β-pleated sheet structures and inhibit aggregation of Aβ. They observed that congo-red, thioflavine and analogues of these molecules also inhibit α-synuclein aggregation. Lee, Lansbury and colleagues (1 3.4) looked at the consequences of aggregate formation. They observed that α-synuclein protofibrils bind to phospholipid vesicles better than does monomeric α-synuclein. Interestingly, they suggest that the protofibrils form a channel that is permeable to calcium, which suggests a novel mechanism of cell death in Lewy body diseases.
A number of groups investigated the subcellular distribution of α-synuclein aggregates. George, Clayton and colleagues (84.11) showed that aggregated α-synuclein associates with the membrane fraction. In contrast, Sharon, Goldberg and Selkoe (84.6) fractionated brain tissue from transgenic mice and lysates from dopaminergic neurons, and they suggest that α-synuclein localizes to the microsomal fraction. Leng, Chase and Bennett (478.18) looked at the distribution of α-synuclein in SY5Y cells and observed that carbachol induces a reversible translocation of α-synuclein from the plasma membrane to cytosolic vesicles. Perez and colleagues (84.15) looked more specifically at the function of α-synuclein and showed that α-synuclein binds to tyrosine hydroxylase and inhibits it activity.
The models of α-synuclein-induced neurodegeneration and Lewy body degeneration are also improving. In a pre-meeting symposium, Greenamyre and colleagues showed that mice treated chronically with the mitochondrial complex I inhibitor, rotenone, develop a syndrome strongly resembling Parkinson’s disease, including production of inclusions resembling Lewy bodies and degeneration of neurons in the substantia nigra (1). M. Lee and colleagues (13.3), Kahle and colleagues (13.6) and Goldberg, Shen and colleagues (84.7) presented a transgenic mouse that develops diffuse pathology in multiple brain areas (including the brain stem, cerebellum and cortex), and which develops pronounced motor deficits. These rodent models will provide a strong basis for future experiments aimed at inhibiting Lewy body pathology.
A number of groups also presented advances in our understanding of parkin. Schlossmacher, Kosik, Selkoe and colleagues (13.7) characterized the distribution of parkin in the brain. They observed that N-terminal anti-parkin antibodies stained virtually all Lewy bodies, suggesting that parkin is a ubiquitous component of Lewy bodies. Tsai, Fishman and Oyler (13.9) and Rankin and colleagues (13.10) both presented evidence from in vitro studies confirming that parkin functions as a ubiquitin ligase. Oyler and colleagues (13.8) examine a specific apoptotic protein that itself appears to be a ubiquitin ligase and suggested that impaired ubiquitin metabolism might stimulate neurodegeneration by altering the levels of proteins that regulate apoptosis. Choi, Wolozin and colleagues (13.11) and Zhang, Dawson and colleagues (476.3) both looked at specific proteins that bind parkin in cells. Both groups identified septins in the hCDCrel family (hCDCrel-1 and 2a) as parkin binding proteins. Zhang, Dawson and colleagues showed that parkin regulates the degradation of hCDCrel-1. This latter work was recently published. Choi, Wolozin and colleagues also identified filamin-1 as a protein that binds parkin. Identification of specific proteins whose catabolism is regulated by parkin will enable more detailed understanding of its function.
13.1 Ueda et al. Identification of α-tubulin as a binding partner of NACP (α-synuclein) and its involvement in Lewy body formation in Parkinson’s disease and in multiple systems atrophy.
13.3 Lee MK et al. Neuronal and behavioral pathology in a transgenic mouse expressing α-synuclein.
13.4 Lee SJ et al., Vesicle binding and permeabilization by nonfibrillar β-sheet containing oligomers of α-synuclein: a trigger for cell death in Parkinson’s disease.
13.5 Ostrerova NV et al., The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity.
13.6 Kahle PJ et al. Subcellular localization of wild-type and Parkinson’s disease associated mutant α-synuclein in human and transgenic mouse brain.
13.7 Schlossmacher MG et al. Characterization of parkin protein in brain and transfected cells.
13.8 Oyler GA et al. XIAP as an E3 ubiquitin ligase in neurodegeneration.
13.9 Tsai Y et al. Parkin functions as an E3 ubiquitin ligase and regulator of the proteosome.
13.10 Rankin CA et al. Parkin has E3 ubiquitin ligase activity.
13.11 Choi P et al. Parkin associates with the actin-binding protein filamin.
84.6 Sharon R et al. A subcellular fractionation study of wt and A53T mutant α-synuclein expressed in transgenic mouse brain and MES 23.5 dopaminergic neuronal cells.
84.7 Goldberg MS et al. Studies of human α-synuclein in transgenic mice.
84.10 Murray IVJ et al. Inhibition of α-synuclein aggregation in vitro.
84.11 George JM et al. α-synuclein self-association inhibits binding to phospholipid membranes.
84.15 Perez RG et al. α-synuclein may be a chaperone for tyrosine hydroxylase.
476.3 Zhang Y et al. Functional characterization of parkin.
478.18 Y Leng, et al. Carbachol stimulation induces α-synuclein translocation from plasma membrane to cytosolic vesicles in SY5Y cells.
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