Accumulating evidence indicates that disturbances in energy production are a leading cause of cellular demise. Oxidative stress, bioenergetic impairment and mitochondrial failure have all been implicated in the etiology of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), as well as retinal degeneration in glaucoma and retinitis pigmentosa. Although we now know that mitochondria are central to these disorders and antioxidants may be able to slow pathogenesis, the precise pathways culminating in neurodegenerative disease are not well defined. Our proposal stems from a remarkable set of preliminary data which we obtained using an innovative mass spectrometry based proteomic approach. We performed a quantitative comparison of peptides found in the presymptomatic retina of the purkinje cell degeneration (pcd) mouse and controls. Upon analysis, the vast majority of abundant and highly significantly changed proteins function in mitochondria or energy production of the cell. In order to validate the results of this state of the art methodology, we propose to examine whether a disruption of cellular metabolic processes is the cause of retinal and cerebellar degeneration in the pcd mouse. Further, we aim to refine our proteomics approach to analyse the changes in purified mitochondria from affected and unaffected mice, to contrast with changes we found in whole tissue lysates. If our hypothesis that Nna1 plays a role in the mitochondria is correct, then it will be the first time that a mammalian zinc carboxypeptidase has been implicated in the function of these core energy organelles. This study should thus identify potential early therapeutic targets for intervention in retinal degeneration. This study will further the efforts to define molecular pathways that lead to the retina degenerating to cause blindness. There is still no cure for most forms of retinal degeneration. A clearer understanding of the processes by which the retina begins to undergo degeneration is essential in order to identify targets for therapy. ? ? ?
| Chakrabarti, Lisa; Zahra, Rabaab; Jackson, Stephen M et al. (2010) Mitochondrial dysfunction in NnaD mutant flies and Purkinje cell degeneration mice reveals a role for Nna proteins in neuronal bioenergetics. Neuron 66:835-47 |
| Chakrabarti, Lisa; Eng, Jeremiah; Ivanov, Nishi et al. (2009) Autophagy activation and enhanced mitophagy characterize the Purkinje cells of pcd mice prior to neuronal death. Mol Brain 2:24 |
| Chakrabarti, Lisa; Eng, Jeremiah; Martinez, Refugio A et al. (2008) The zinc-binding domain of Nna1 is required to prevent retinal photoreceptor loss and cerebellar ataxia in Purkinje cell degeneration (pcd) mice. Vision Res 48:1999-2005 |
