The overall goal of this proposal is to clarify mechanistic pathobiological events underlying Lewy body (LB) dementias ? a dementing illness with cognitive impairment that affects more than a million Americans. An established molecular player in LB dementia is the small presynaptic protein ?-synuclein. Amongst a plethora of incriminating evidence, genomic multiplications and mutations of ?-synuclein are seen in families harboring these diseases; and it has been long recognized that understanding the mechanistic events that lead to ?-synuclein-mediated toxicity in LB dementia is of utmost importance. For over a decade, a primary focus in the field has been to decipher the normal function of ?-synuclein, with the ultimate goal of understanding transition to pathologic states. However, despite considerable effort, the precise mechanisms underlying the normal function of ?-synuclein, and early triggers leading to pathologic aggregation remain elusive. The basis of our proposal is a series of pilot experiments, where we uncovered novel roles for two functional partners of ?-synuclein, and we hypothesize that abnormalities in these associations are the initial pathologic triggers for LB dementias. Previous work from us and others has helped shape a consensus that ?-synuclein is a physiologic attenuator of neurotransmitter release, though underlying mechanistic events are unclear. In these previous studies, we proposed a model where ?-syn organizes into higher-order multimers that physiologically tether synaptic vesicles (SVs) ? leading to a diminution in SV-mobilization, SV-recycling, and consequently, neurotransmitter release. In new pilot experiments, we discovered novel roles for two other presynaptic proteins ? VAMP2 and synapsin ? in helping ?-synuclein attenuate neurotransmission. Eventually, our data led us to a working model where synapsin and VAMP2 play sequential roles in executing ?-synuclein function. Tenets of this model will be tested in Aims 1/2. Additionally, an emerging idea in the field is that disruption of physiologic associations might allow free ?-synuclein monomers to aggregate ? triggering pathology ? and that this might be one of the earliest pathologic events in disease; however, in vivo evidence is lacking. Leveraging our discoveries on functional ?-synuclein partners, Aims 2/3 will ask if a disruption of these associations might also accelerate pathology in cellular and animal models of LB dementias.
Our aims are:
Aim #1 : Identify the role of VAMP2 in ?-synuclein mediated synaptic attenuation.
Aim #2 : Identify the role of synapsin in ?-synuclein mediated synaptic attenuation and pathology.
Aim #3 : Test the hypothesis that disrupting physiologic associations can trigger ?-synuclein pathology in vivo. Upon completion, our studies should reveal vital clues into the normal function of ?-synuclein, as well as events that trigger dementia and cognitive impairment in these devastating illnesses.
The small presynaptic protein alpha-synuclein (?-syn) has established roles in a variety of dementias including dementia with Lewy bodies (DLB), collectively called synucleinopathies. We have proposed a model where ?- syn acts as a physiologic attenuator of neurotransmission, but mechanisms underlying its normal function and initial pathologic triggers are uncertain. We identified novel roles for other synaptic proteins in helping ?-syn execute its function, which is the basis of this proposal. Leveraging this new knowledge, we will also test an emerging hypothesis in the field that disruption of physiologic interactions is one of the earliest triggers of disease.
