Reversing Parkinson's Symptoms

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by SangeetaG
Last updated 5 years ago

Discipline:
Science
Subject:
Human Anatomy

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Reversing Parkinson's Symptoms

Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra. In particular, the onset of familial PD is due to a mutation in PARKIN, a protein that is unique to the ubiquitin E3 ligase. The ubiquitin E3 ligase is responsible for targeting degradation of proteins via a lysine 48 ubiquitination tag. However, ligase inactivity (via PARKIN mutations) causes an accumulation of proteins such as aminoacyl-tRNA synthetase complex interacting multifunctional protein-2 (AIMP2). Thus, the authors hypothesized, an accumulation of AIMP2 should lead to degeneration of dopaminergic neurons and symptoms resembling PD. The purpose of the experiment was to investigate the role of AIMP2 in PD and the signalling cascade by which it acts.

Reversing Parkinson’s symptoms with PARP1 inhibitors

Dopaminergic Neurons

Parkinson's Disease

Activated dopamine neurons

Substantia Nigra

Rotarod Assay

By using AIMP2 transgenic mice, Lee et al. found that an accumulation of AIMP2 selectively targeted dopaminergic neurons of the ventral tegmental area and the substantia nigra. Increased levels of AIMP2 also impaired the motor ability of the AIMP2 transgenic mice during the rotarod assay, thus proving that an accumulation of AIMP2 is a factor for the progression of PD. They also found that overexpression of AIMP2 in dopaminergic neurons resulted in direct activation of poly(ADP-ribose) polymerase-1 (PARP1) which facilitated degeneration of these neurons via parthanatos (a cellular death mechanism). However, PARP1 knockout mice and PARP1 inhibitors protected dopaminergic neurons, thus suggesting that PARP1 inhibitors could be used as a potential treatment for PD.

Parthanatos

Sources:Substantia nigra and parkinson's disease: http://www.nlm.nih.gov/medlineplus/ency/imagepages/19515.htmMolecular mechanisms underlying cell death in spinal networks in relation to locomotor activity after acute injury in vitro: http://journal.frontiersin.org/Journal/10.3389/fncel.2011.00009/fullA major breakthrough in treating Parkinson's Disease cannot reach patients: http://siberiantimes.com/science/casestudy/news/a-major-breakthrough-in-treating-parkinsons-disease-cannot-reach-patients/Parkinson's Disease: Mechanisms and Models: http://www.sciencedirect.com/science/article/pii/S0896627303005683Dopaminergic neurons: http://www.sciencedirect.com/science/article/pii/S1357272504003711Parthanatos, a messenger of death: https://www.bioscience.org/2009/v14/af/3297/fulltext.htmTests to assess motor phenotype in mice: a user's guide: http://www.nature.com/nrn/journal/v10/n7/fig_tab/nrn2652_F1.htmlParthanatos Mediates AIMP2 Activated Age Dependent Dopaminergic Neuronal Loss: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3785563/

apoptosis inducing factor ∙ death

DNA nicks ∙ excess PARP1


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