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Parkinson Disease: HELP
Articles by Todd P. Logan
Based on 4 articles published since 2008
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Between 2008 and 2019, Todd Logan wrote the following 4 articles about Parkinson Disease.
 
+ Citations + Abstracts
1 Article α-Synuclein promotes dilation of the exocytotic fusion pore. 2017

Logan, Todd / Bendor, Jacob / Toupin, Chantal / Thorn, Kurt / Edwards, Robert H. ·Departments of Neurology and Physiology, UCSF School of Medicine, University of California, San Francisco, San Francisco, California, USA. · Graduate Program in Biomedical Sciences, UCSF School of Medicine, University of California, San Francisco, San Francisco, California, USA. · Department of Biochemistry &Biophysics, UCSF School of Medicine, University of California, San Francisco, San Francisco, California, USA. ·Nat Neurosci · Pubmed #28288128.

ABSTRACT: The protein α-synuclein has a central role in the pathogenesis of Parkinson's disease. Like that of other proteins that accumulate in neurodegenerative disease, however, the function of α-synuclein remains unknown. Localization to the nerve terminal suggests a role in neurotransmitter release, and overexpression inhibits regulated exocytosis, but previous work has failed to identify a clear physiological defect in mice lacking all three synuclein isoforms. Using adrenal chromaffin cells and neurons, we now find that both overexpressed and endogenous synuclein accelerate the kinetics of individual exocytotic events, promoting cargo discharge and reducing pore closure ('kiss-and-run'). Thus, synuclein exerts dose-dependent effects on dilation of the exocytotic fusion pore. Remarkably, mutations that cause Parkinson's disease abrogate this property of α-synuclein without impairing its ability to inhibit exocytosis when overexpressed, indicating a selective defect in normal function.

2 Article The function of α-synuclein. 2013

Bendor, Jacob T / Logan, Todd P / Edwards, Robert H. ·Departments of Neurology and Physiology, Graduate Programs in Biomedical Sciences, Cell Biology and Neuroscience, UCSF School of Medicine, San Francisco, CA 94158-2517, USA. ·Neuron · Pubmed #24050397.

ABSTRACT: Human genetics has indicated a causal role for the protein α-synuclein in the pathogenesis of familial Parkinson's disease (PD), and the aggregation of synuclein in essentially all patients with PD suggests a central role for this protein in the sporadic disorder. Indeed, the accumulation of misfolded α-synuclein now defines multiple forms of neural degeneration. Like many of the proteins that accumulate in other neurodegenerative disorders, however, the normal function of synuclein remains poorly understood. In this article, we review the role of synuclein at the nerve terminal and in membrane remodeling. We also consider the prion-like propagation of misfolded synuclein as a mechanism for the spread of degeneration through the neuraxis.

3 Article Engineered disulfide bonds restore chaperone-like function of DJ-1 mutants linked to familial Parkinson's disease. 2010

Logan, Todd / Clark, Lindsay / Ray, Soumya S. ·Center for Neurologic Diseases, Brigham and Women's Hospital, Boston,Massachusetts 02115, USA. ·Biochemistry · Pubmed #20527929.

ABSTRACT: Loss-of-function mutations such as L166P, A104T, and M26I in the DJ-1 gene (PARK7) have been linked to autosomal-recessive early onset Parkinson's disease (PD). Cellular and structural studies of the familial mutants suggest that these mutations may destabilize the dimeric structure. To look for common dynamical signatures among the DJ-1 mutants, short MD simulations of up to 1000 ps were conducted to identify the weakest region of the protein (residues 38-70). In an attempt to stabilize the protein, we mutated residue Val 51 to cysteine (V51C) to make a symmetry-related disulfide bridge with the preexisting Cys 53 on the opposite subunit. We found that the introduction of this disulfide linkage stabilized the mutants A104T and M26I against thermal denaturation, improved their ability to scavenge reactive oxygen species (ROS), and restored a chaperone-like function of blocking alpha-synuclein aggregation. The L166P mutant was far too unstable to be rescued by introduction of the V51C mutation. The results presented here point to the possible development of pharmacological chaperones, which may eventually lead to PD therapeutics.

4 Article Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease. 2009

Liu, Zhihua / Meray, Robin K / Grammatopoulos, Tom N / Fredenburg, Ross A / Cookson, Mark R / Liu, Yichin / Logan, Todd / Lansbury, Peter T. ·Center for Neurologic Diseases, Brigham and Women's Hospital and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA. ·Proc Natl Acad Sci U S A · Pubmed #19261853.

ABSTRACT: Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is linked to Parkinson's disease (PD) and memory and is selectively expressed in neurons at high levels. Its expression pattern suggests a function distinct from that of its widely expressed homolog UCH-L3. We report here that, in contrast to UCH-L3, UCH-L1 exists in a membrane-associated form (UCH-L1(M)) in addition to the commonly studied soluble form. C-terminal farnesylation promotes the association of UCH-L1 with cellular membranes, including the endoplasmic reticulum. The amount of UCH-L1(M) in transfected cells is shown to correlate with the intracellular level of alpha-synuclein, a protein whose accumulation is associated with neurotoxicity and the development of PD. Reduction of UCH-L1(M) in cell culture models of alpha-synuclein toxicity by treatment with a farnesyltransferase inhibitor (FTI-277) reduces alpha-synuclein levels and increases cell viability. Proteasome function is not affected by UCH-L1(M), suggesting that it may negatively regulate the lysosomal degradation of alpha-synuclein. Therefore, inhibition of UCH-L1 farnesylation may be a therapeutic strategy for slowing the progression of PD and related synucleinopathies.