RAB7L1 Interacts with LRRK2 to Modify Intraneuronal Protein Sorting and Parkinson's Disease Risk.
ABSTRACT Recent genome-wide association studies have linked common variants in the human genome to Parkinson's disease (PD) risk. Here we show that the consequences of variants at 2 such loci, PARK16 and LRRK2, are highly interrelated, both in terms of their broad impacts on human brain transcriptomes of unaffected carriers, and in terms of their associations with PD risk. Deficiency of the PARK16 locus gene RAB7L1 in primary rodent neurons, or of a RAB7L1 ortholog in Drosophila dopamine neurons, recapitulated degeneration observed with expression of a familial PD mutant form of LRRK2, whereas RAB7L1 overexpression rescued the LRRK2 mutant phenotypes. PD-associated defects in RAB7L1 or LRRK2 led to endolysosomal and Golgi apparatus sorting defects and deficiency of the VPS35 component of the retromer complex. Expression of wild-type VPS35, but not a familial PD-associated mutant form, rescued these defects. Taken together, these studies implicate retromer and lysosomal pathway alterations in PD risk.
SourceAvailable from: Simona Eleuteri[Show abstract] [Hide abstract]
ABSTRACT: Parkinson's disease (PD) is a common neurodegenerative disorder. Functional interactions between some PD genes, like PINK1 and parkin, have been identified, but whether other ones interact remains elusive. Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. We also show interactions between VPS35, EIF4G1, and α-synuclein, a protein with a key role in PD. We extend our findings from yeast to an animal model and show that these interactions are conserved in neurons and in transgenic mice. Our studies reveal unexpected genetic and functional interactions between two seemingly unrelated PD genes and functionally connect them to α-synuclein pathobiology in yeast, worms, and mouse. Finally, we provide a resource of candidate PD genes for future interrogation. Copyright © 2015 Elsevier Inc. All rights reserved.Neuron 12/2014; 85(3). DOI:10.1016/j.neuron.2014.11.027 · 15.98 Impact Factor
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ABSTRACT: Parkinson's disease is primarily a movement disorder with predilection for the nigral dopaminergic neurons and is often associated with widespread neurodegeneration and diffuse Lewy body deposition. Recent advances in molecular genetics and studies in model organisms have transformed our understanding of Parkinson's pathogenesis and suggested unifying biochemical pathways despite the clinical heterogeneity of the disease. In this review, we summarized the evidence that a number of Parkinson's associated genetic mutations or polymorphisms (LRRK2, VPS35, GBA, ATP13A2, ATP6AP2, DNAJC13/RME-8, RAB7L1, GAK) disrupt protein trafficking and degradation via the endosomal pathway and discussed how such defects could arise from or contribute to the accumulation and misfolding of α-synuclein in Lewy bodies. We propose that an age-related pathological depletion of functional endolysosomes due to neuromelanin deposition in dopaminergic neurons may increase their susceptibility to stochastic molecular defects in this pathway and we discuss how enzymes that regulate ubiquitin signalling, as exemplified by the ubiquitin ligase Nedd4, could provide the missing link between genetic and acquired defects in endosomal trafficking. Copyright © 2015. Published by Elsevier Inc.Molecular and Cellular Neuroscience 02/2015; DOI:10.1016/j.mcn.2015.02.009 · 3.73 Impact Factor
Article: Fruit Flies in Biomedical Research.[Show abstract] [Hide abstract]
ABSTRACT: Many scientists complain that the current funding situation is dire. Indeed, there has been an overall decline in support in funding for research from the National Institutes of Health and the National Science Foundation. Within the Drosophila field, some of us question how long this funding crunch will last as it demotivates principal investigators and perhaps more importantly affects the longterm career choice of many young scientists. Yet numerous very interesting biological processes and avenues remain to be investigated in Drosophila, and probing questions can be answered fast and efficiently in flies to reveal new biological phenomena. Moreover, Drosophila is an excellent model organism for studies that have translational impact for genetic disease and for other medical implications such as vector-borne illnesses. We would like to promote a better collaboration between Drosophila geneticists/biologists and human geneticists/bioinformaticians/clinicians, as it would benefit both fields and significantly impact the research on human diseases. Copyright © 2015, The Genetics Society of America.Genetics 01/2015; DOI:10.1534/genetics.114.171785 · 4.87 Impact Factor