Mitochondrial dysfunction has been identified as one of the key players in Parkinson's disease (PD) pathogenesis. While the etiology is unknown in most cases, the development of progressive parkinsonian symptoms has been shown in patients following exposure to various environmental and occupational toxins. Numerous studies demonstrate that these neurotoxins specifically inhibit the mitochondrial respiratory chain complexes of dopaminergic neurons, which initiates a cascade of events ultimately leading to cell death. Furthermore, the susceptibility to environmental neurotoxins is increased in the aged nervous system. Thus for the long-term treatment of PD and parkinsonian symptoms, therapeutic strategies are needed that not only restore dopaminergic neuron function, but also provide mitochondrial protection and restoration from various stresses, including environmental toxin exposure. In the past, neurotrophic growth factors have received considerable attention as potential therapeutic agents for neurological disorders. However, the clinical application of these native molecules has not advanced primarily due to pharmacological disadvantages and challenges associated with directly delivering large protein molecules to the brain. The emergence of physiologically functional propeptides from the neurotrophic factor family provides a wealth of novel, smaller sequences for biotherapeutic exploration and evaluation. Examination of the glial cell line-derived neurotrophic factor (GDNF) prosequence predicts internal dibasic endopeptidase sites that would yield a smaller, amidated eleven amino acid residue peptide named dopamine neuron stimulating peptide-11 (DNSP-11). Recent evaluation of DNSP-11 has shown that it exhibits similar GDNF-like neurotrophic responses in normal and parkinsonian rat models. However, cell culture and proteomic pull-down data suggest that DNSP-11 functions differently than mature GDNF;leading to our hypothesis that DNSP-11's neurobiological actions are through the mitochondria. The research outlined in the current proposal will measure DNSP-11's bioenergetic and protective effects, in the MN9D dopaminergic cell line, from toxins that specifically target the mitochondrial respiratory complexes. The information obtained in this study will further our understanding of this propeptide's neurobiological activity and provide the basis for future evaluation and biotherapeutic development of DNSP-11.

Public Health Relevance

Parkinson's disease (PD), a chronic neurological disorder that affects over 1 million Americans, is characterized by stooped posture, balance impairments, rigidity, resting hand tremors, and bradykinesia. While the cause of PD is largely unknown, parkinsonian symptoms have been shown to develop following long-term exposure to common environmental toxins that specifically target the mitochondria of dopamine neurons. The goal of this pilot project is to investigate the neuroprotective properties of a novel neurotrophic propeptide, DNSP-11, from mitochondrial-specific toxins to pave the way for its downstream evaluation as a potential PD therapeutic.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Research Grants (R03)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Sieber, Beth-Anne
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University of Kentucky
Anatomy/Cell Biology
Schools of Medicine
United States
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Stenslik, Mallory J; Potts, Lisa F; Sonne, James W H et al. (2015) Methodology and effects of repeated intranasal delivery of DNSP-11 in a rat model of Parkinson's disease. J Neurosci Methods 251:120-9
Fuqua, Joshua L; Littrell, Ofelia M; Lundblad, Martin et al. (2014) Dynamic changes in dopamine neuron function after DNSP-11 treatment: effects in vivo and increased ERK 1/2 phosphorylation in vitro. Peptides 54:1-8
Littrell, O M; Fuqua, J L; Richardson, A D et al. (2013) A synthetic five amino acid propeptide increases dopamine neuron differentiation and neurochemical function. Neuropeptides 47:43-9