Discovering mechanism-based treatments for PD, dementia with Lewy Bodies (DLB), and related a-synucleinopathies is an enormous medical need and a central mission of NINDS. Genetic and neuropathological data implicate accumulation of aS as an essential feature of both idiopathic and sporadic PD. aS missense mutations, increased gene dosage, and certain 5? or 3? UTR regulatory alleles can each significantly heighten PD risk. In 2011, we applied non-denaturing methods to identify a hitherto unrecognized form of cellular aS: a-helical tetramers. This finding raised controversy because two decades of in vitro work on recombinant aS indicated it occurred as a ?natively unfolded? monomer, and because the helical tetramers cannot be observed by any biochemical method that breaks open cells, as that rapidly disassembles the native tetramers. Accordingly, our initial R01 application was not funded because the reviewers stated the tetramer hypothesis was ?too controversial? to warrant NIH funding. An appeal to NINDS Council that this did not reflect NIH guidance on seeking scientific novelty led to an SEP review resulting in a different view: the new concept should be pursued, especially by those who initiated it. About a dozen labs have subsequently published evidence for the existence of aS tetramers. During this first grant period, we have analyzed the complex T:M equilibrium in health and PD. We found that all fPD missense mutations significantly lower the T:M ratio, including in human neurons. The Ko lab (Hopkins) then discovered that Gaucher?s GBA mutations lower the aS T:M ratio in human neurons. Given this progress, we now wish to extend this entirely novel hypothesis to answer certain key questions relevant to PD, DLB and AD. Our proposed new experiments will be enabled by our having just generated a unique mouse model in which E46K-like, tetramer-abrogating aS mutations cause biochemical, neuropathological and motor phenotypes strikingly resembling PD. We will address 3 distinct Aims. 1. Deeply phenotype the age- and gender-related temporal development of the PD-like biochemical, neuropathological and motor syndromes of our 3K vs. 1K vs. hu WT tg mice. We will pay special attention to the emerging but unsettled evidence that clusters of membrane vesicles may be the precursors of filamentous Lewy-type bodies that are late-stage lesions. 2. Examine the role of fatty acid saturation and the key cellular desaturase, SCD, as a modulator of the normal aS tetramer:monomer equilibrium in vivo. We will use both genetic and pharmacological lowering of SCD activity to learn if this ameliorates the T:M shift of fPD mutant mice and its many downstream consequences. 3. Ask if our new hypothesis of a possible shared T:M mechanism for aS dyshomeostasis applies to three forms of fPD by a) creating the first mouse with G51D and its amplification as a ?3D? mutant; b) extending the discovery of GBA mutations in lowering the T:M ratio; and c) asking if LRRK2 mutations may also alter the aS T:M equilibrium in neurons. These distinct but thematically related Aims and the unexpected data that will flow from them should advance the basic science and therapeutics of PD & DLB.

Public Health Relevance

Many brain diseases are characterized by ?misfolding? and progressive aggregation of otherwise soluble proteins. To decipher the molecular basis of such a disease and devise effective therapies, one should know the normal biology of the responsible protein. In Parkinson's disease (PD) and certain related disorders, ?- synuclein accumulates in neurons. Since its discovery 20 years ago, ?Syn has been defined as a ?naturally unfolded? protein. In contrast, we discovered in 2011 that the major cellular form of ?Syn is a helically-folded tetramer. Here, we propose many novel experiments to elucidate the complex relationship between the newly discovered helical tetramer, the unfolded monomer, and misfolded aggregates that are neurotoxic in PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS083845-06
Application #
9818068
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Sieber, Beth-Anne
Project Start
2014-02-01
Project End
2025-02-28
Budget Start
2020-03-02
Budget End
2021-02-28
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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