The objective of the proposed research is to elucidate the role of Rab proteins in ?-synuclein toxicity. Alpha- synuclein (?Syn) is a principal component of Lewy bodies found pathologically in Parkinson disease (PD) and related disorders, such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Abnormal folding, aggregation, and deposition of ?Syn are believed to be central to development of neuronal dysfunction and degeneration. Recent data in yeast indicate that overexpression of ?Syn interferes with intracellular trafficking and results in abnormal vesicle accumulation, clustering, and toxicity. Rab proteins are members of the Ras super-family of small GTP-binding proteins and have critical functions in intracellular trafficking, membrane transport, and even neurotransmitter release. Overexpression of Rab proteins in several PD models, including yeast, worms, and flies, as well as rodent primary neurons, rescues ?Syn toxicity. Moreover, Rab proteins show increased binding to ?Syn in several neurodegenerative disorders, including DLB, MSA, and possibly also PD. Oligomeric forms of mutant ?Syn likewise appear to have increased Rab binding. Our own preliminary data confirm Rab proteins'protective role, and show that they also reduce the amount of oligomeric forms of ?Syn present in cell models of ?Syn toxicity. Together, these findings support the hypothesis that accumulation of ?Syn interferes with normal Rab function, leading to toxicity via disruption of intracellular trafficking. Alternatively, specific Rab proteins may normally protect against formation and accumulation of toxic ?Syn species, but are overwhelmed by overexpression in model systems and pathological conditions, such as PD. Enhancing Rab function may thus provide a new therapeutic opportunity for PD and related neurodegenerative disorders. The proposed experiments will therefore discern the mechanisms whereby Rab overexpression confers protection against ?Syn. My long-term goal is to develop a career aimed at understanding and ultimately finding novel therapies for PD and related neurodegenerative disorders through basic and translational research. The proposed research and career development plan, under the supervision of Dr. Bradley Hyman, will help achieve my immediate goals to obtain up-to-date molecular and genetic skills and to learn state-of-the-art imaging techniques to complement my strong neuroanatomical background. Additional expertise in viral manipulation and CNS gene delivery methods from Drs. Xandra Breakefield and Miguel Esteves will also forward my goal of eventually becoming a gene therapy expert and translating my work into potential patient therapies. Developing these research skills, along with my continued clinical training and experience are critical to becoming a successful, independent clinician-scientist committed to translational neuroscience.
The results of the proposed research are particularly relevant and critical to understanding the role of ?- synuclein in Parkinson disease and related neurodegenerative disorders. The proposed studies will test the hypothesis that ?-synuclein interferes with Rab protein function and intracellular trafficking, leading to neuronal dysfunction and toxicity. Furthermore, overexpression of Rabs may ameliorate this toxicity.
|Planetta, Peggy J; Ofori, Edward; Pasternak, Ofer et al. (2016) Free-water imaging in Parkinson's disease and atypical parkinsonism. Brain 139:495-508|
|Burciu, Roxana G; Chung, Jae Woo; Shukla, Priyank et al. (2016) Functional MRI of disease progression in Parkinson disease and atypical parkinsonian syndromes. Neurology 87:709-17|
|Falchook, Adam D; Salazar, Liliana; Neal, Dan et al. (2015) Global attentional neglect of segmented lines in Parkinson's disease. Neurocase 21:501-8|
|Amano, Shinichi; Skinner, Jared W; Lee, Hyo Keun et al. (2015) Discriminating features of gait performance in progressive supranuclear palsy. Parkinsonism Relat Disord 21:888-93|
|Ceballos-Diaz, Carolina; Rosario, Awilda M; Park, Hyo-Jin et al. (2015) Viral expression of ALS-linked ubiquilin-2 mutants causes inclusion pathology and behavioral deficits in mice. Mol Neurodegener 10:25|
|McFarland, Nikolaus R; Dimant, Hemi; Kibuuka, Laura et al. (2014) Chronic treatment with novel small molecule Hsp90 inhibitors rescues striatal dopamine levels but not Î±-synuclein-induced neuronal cell loss. PLoS One 9:e86048|
|Planetta, Peggy J; McFarland, Nikolaus R; Okun, Michael S et al. (2014) MRI reveals brain abnormalities in drug-naive Parkinson's disease. Exerc Sport Sci Rev 42:12-22|
|Dimant, Hemi; Kalia, Suneil K; Kalia, Lorraine V et al. (2013) Direct detection of alpha synuclein oligomers in vivo. Acta Neuropathol Commun 1:6|
|McFarland, Nikolaus R; Burdett, Thomas; Desjardins, Cody A et al. (2013) Postmortem brain levels of urate and precursors in Parkinson's disease and related disorders. Neurodegener Dis 12:189-98|
|McFarland, Nikolaus R; Okun, Michael S (2013) Movement disorders in 2012: Advancing research towards novel therapeutic approaches. Nat Rev Neurol 9:70-1|
Showing the most recent 10 out of 14 publications