Parkinson?s disease (PD) is the second most common late-onset neurodegenerative disease with the largest relative increase in mortality rates among all neurological disorders. PD is traditionally considered a motor disorder, characterized by the loss of dopaminergic neurons of the SNpc, and the presence of fibrillar cytoplasmic inclusions called Lewy bodies and Lewy neurites. However, a more global perspective on the PD is developing, motivated by pathological and clinical findings that extend beyond the basal ganglia. In particular, the majority of PD patients meet criteria for a secondary diagnosis of mild cognitive impairment that progresses dementia, a significant contributor to disease morbidity and mortality. The emerging view is that the abnormalities in ?-synuclein (?S) may be responsible for motor and non-motor symptoms in PD and Dementia with Lewy Bodies (DLB). Significantly, we recently found that abnormal ?S can cause post-synaptic deficits in vitro and in vivo via a microtubule associated protein tau (MAPT) dependent mechanism. In this proposal, we will directly determine the following hypothesis: 1) Pathogenic ?S species produce cognitive decline tau-dependent post-synaptic mechanisms and 2) MAPT-dependent postsynaptic deficits caused by exogenous ?S fibrils/oligomers contribute to cognitive deficits in sporadic PD and DLB. To determine the mechanistic basis for cognitive deficits in ?-synucleinopathy, we propose following aims: 1) Determine whether tau is required for ?S dependent synaptic and cognitive deficits; 2) Determine if mutant ?S-dependent AMPAR deficits and memory deficits are caused by multiple pathways; 3) Determine whether hippocampal ?S pathology and somatodendritic tau mislocalization correlates with dementia in PD; 4) Determine if exogenous pathogenic ?S induces pre- and/or post-synaptic deficits; and 5) Determine if pathogenic ?S induces defects in synaptic plasticity and memory in a tau dependent manner.
While dementia is a significant disability associated with PD and DLB, there are no effective therapies for slowing or reversing progressive cognitive deficit in PD. Proposed studies will provide mechanistic understanding of how ?-synuclein abnormalities lead to synaptic deficits and cognitive deficits. Information generated will have direct impact on future efforts aimed at developing therapies for PD.
|Teravskis, Peter J; Covelo, Ana; Miller, Eric C et al. (2018) A53T Mutant Alpha-Synuclein Induces Tau-Dependent Postsynaptic Impairment Independently of Neurodegenerative Changes. J Neurosci 38:9754-9767|