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Parkinson Disease: HELP
Articles by Bryan A. Martinez
Based on 4 articles published since 2010
(Why 4 articles?)
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Between 2010 and 2020, B. A. Martinez wrote the following 4 articles about Parkinson Disease.
 
+ Citations + Abstracts
1 Review C. elegans as a model system to accelerate discovery for Parkinson disease. 2017

Martinez, Bryan A / Caldwell, Kim A / Caldwell, Guy A. ·Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA. · Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA. Electronic address: gcaldwel@ua.edu. ·Curr Opin Genet Dev · Pubmed #28242493.

ABSTRACT: The nematode Caenorhabditis elegans possesses a wealth of opportunities to explore mechanisms which regulate metazoan complexity, basic cellular biology, and neuronal system attributes. Together, these provide a basis for tenable understanding of neurodegenerative disorders such as Parkinson disease (PD) through functional genomic analysis and pharmacological manipulation for the discovery of previously unknown genetic and environmental risk factors. The application of C. elegans has proven prescient in terms of the elucidation of functional effectors of cellular mechanisms underlying PD that translate to mammals. The current state of PD research using C. elegans encompasses defining obscure combinatorial interactions between genes or between genes and the environment, and continues to provide opportunities for the discovery of new therapeutic targets and disease-modifying drugs.

2 Article Dysregulation of the Mitochondrial Unfolded Protein Response Induces Non-Apoptotic Dopaminergic Neurodegeneration in 2017

Martinez, Bryan A / Petersen, Daniel A / Gaeta, Anthony L / Stanley, Samuel P / Caldwell, Guy A / Caldwell, Kim A. ·Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama 35487. · Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama 35487 kcaldwel@ua.edu. ·J Neurosci · Pubmed #29030433.

ABSTRACT: Due to environmental insult or innate genetic deficiency, protein folding environments of the mitochondrial matrix are prone to dysregulation, prompting the activation of a specific organellar stress-response mechanism, the mitochondrial unfolded protein response (UPR

3 Article Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. 2014

Jackrel, Meredith E / DeSantis, Morgan E / Martinez, Bryan A / Castellano, Laura M / Stewart, Rachel M / Caldwell, Kim A / Caldwell, Guy A / Shorter, James. ·Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. · Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. · Department of Biological Sciences, University of Alabama, Tuscaloosa, AL 35487, USA. · Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. · Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: jshorter@mail.med.upenn.edu. ·Cell · Pubmed #24439375.

ABSTRACT: There are no therapies that reverse the proteotoxic misfolding events that underpin fatal neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Hsp104, a conserved hexameric AAA+ protein from yeast, solubilizes disordered aggregates and amyloid but has no metazoan homolog and only limited activity against human neurodegenerative disease proteins. Here, we reprogram Hsp104 to rescue TDP-43, FUS, and α-synuclein proteotoxicity by mutating single residues in helix 1, 2, or 3 of the middle domain or the small domain of nucleotide-binding domain 1. Potentiated Hsp104 variants enhance aggregate dissolution, restore proper protein localization, suppress proteotoxicity, and in a C. elegans PD model attenuate dopaminergic neurodegeneration. Potentiating mutations reconfigure how Hsp104 subunits collaborate, desensitize Hsp104 to inhibition, obviate any requirement for Hsp70, and enhance ATPase, translocation, and unfoldase activity. Our work establishes that disease-associated aggregates and amyloid are tractable targets and that enhanced disaggregases can restore proteostasis and mitigate neurodegeneration.

4 Article Mitochondrial dysfunction, oxidative stress, and neurodegeneration elicited by a bacterial metabolite in a C. elegans Parkinson's model. 2014

Ray, A / Martinez, B A / Berkowitz, L A / Caldwell, G A / Caldwell, K A. ·Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA. · 1] Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA [2] Departments of Neurobiology and Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USA. ·Cell Death Dis · Pubmed #24407237.

ABSTRACT: Genetic and idiopathic forms of Parkinson's disease (PD) are characterized by loss of dopamine (DA) neurons and typically the formation of protein inclusions containing the alpha-synuclein (α-syn) protein. Environmental contributors to PD remain largely unresolved but toxins, such as paraquat or rotenone, represent well-studied enhancers of susceptibility. Previously, we reported that a bacterial metabolite produced by Streptomyces venezuelae caused age- and dose-dependent DA neurodegeneration in Caenorhabditis elegans and human SH-SY5Y neurons. We hypothesized that this metabolite from a common soil bacterium could enhance neurodegeneration in combination with PD susceptibility gene mutations or toxicants. Here, we report that exposure to the metabolite in C. elegans DA neurons expressing human α-syn or LRRK2 G2019S exacerbates neurodegeneration. Using the PD toxin models 6-hydroxydopamine and rotenone, we demonstrate that exposure to more than one environmental risk factor has an additive effect in eliciting DA neurodegeneration. Evidence suggests that PD-related toxicants cause mitochondrial dysfunction, thus we examined the impact of the metabolite on mitochondrial activity and oxidative stress. An ex vivo assay of C. elegans extracts revealed that this metabolite causes excessive production of reactive oxygen species. Likewise, enhanced expression of a superoxide dismutase reporter was observed in vivo. The anti-oxidant probucol fully rescued metabolite-induced DA neurodegeneration, as well. Interestingly, the stress-responsive FOXO transcription factor DAF-16 was activated following exposure to the metabolite. Through further mechanistic analysis, we discerned the mitochondrial defects associated with metabolite exposure included adenosine triphosphate impairment and upregulation of the mitochondrial unfolded protein response. Metabolite-induced toxicity in DA neurons was rescued by complex I activators. RNA interference (RNAi) knockdown of mitochondrial complex I subunits resulted in rescue of metabolite-induced toxicity in DA neurons. Taken together, our characterization of cellular responses to the S. venezuelae metabolite indicates that this putative environmental trigger of neurotoxicity may cause cell death, in part, through mitochondrial dysfunction and oxidative stress.