Mak S.K.,Parkinsons Institute |
McCormack A.L.,SRI International |
Manning-Bog A.B.,SRI International |
Cuervo A.M.,Yeshiva University |
Di Monte D.A.,SRI International
Journal of Biological Chemistry | Year: 2010
Pathologic accumulation of α-synuclein is a feature of human parkinsonism and other neurodegenerative diseases. This accumulation may be counteracted by mechanisms of protein degradation that have been investigated in vitro but remain to be elucidated in animal models. In this study, lysosomal clearance of α-synuclein in vivo was indicated by the detection of α-synuclein in the lumen of lysosomes isolated from the mouse midbrain. When neuronal α-synuclein expression was enhanced as a result of toxic injury (i.e. treatment of mice with the herbicide paraquat) or transgenic protein overexpression, the intralysosomal content of α-synuclein was also significantly increased. This effect was paralleled by a marked elevation of the lysosome-associated membrane protein type 2A (LAMP-2A) and the lysosomal heat shock cognate protein of 70 kDa (hsc70), two essential components of chaperone-mediated autophagy (CMA). Immunofluorescence microscopy revealed an increase in punctate (lysosomal) LAMP-2A staining that co-localized with α-synuclein within nigral dopaminergic neurons of paraquat-treated and α-synuclein-overexpressing animals. The data provide in vivo evidence of lysosomal degradation of α-synuclein under normal conditions and, quite importantly, under conditions of enhanced protein burden. In the latter, increased lysosomal clearance of α-synuclein was mediated, at least in part, by CMA induction. It is conceivable that these neuronal mechanisms of protein clearance play an important role in neurodegenerative processes characterized by abnormal α-synuclein buildup. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Source
Marras C.,University of Toronto |
Goldman S.M.,Parkinsons Institute
Seminars in Neurology | Year: 2011
The vast majority of disease is due to complex relationships between genetic and environmental factors. Single genetic or environmental causes are rare. Unfortunately, this presents major challenges for assessing disease risk in individuals. Further complicating the situation is the fact that there are many ways in which genetic and environmental determinants can combine to cause disease. This review explores the concepts of geneenvironment interaction to provide a basic understanding of the principles of interactions and approaches to studying them. Collaborations between genetics and environmental experts will be crucial to understand the complex relationships. Copyright © 2011 by Thieme Medical Publishers, Inc. Source
Stanford University and Parkinsons Institute | Date: 2013-12-06
Methods of generating cell lines with a sequence variation or copy number variation of a gene of interest, methods of use thereof, and cell lines with a sequence variation or copy number variation of a gene of interest are provided.
Parkinsons Institute | Date: 2015-09-29
Disclosed are novel phosphorylation sites identified in LRRK2 and associated with Parkinsons Disease, antibodies that specifically bind to the novel phosphorylation sites, and laboratory and clinical uses thereof.
Neuraltus Pharmaceuticals, Parkinsons Institute and The Hospital For Sick Children | Date: 2014-06-16
Compositions and methods are provided for treating a disorder characterized by -synuclein dysfunction and/or altered lipid metabolism.