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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS108686-04
Application #
10112975
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sieber, Beth-Anne
Project Start
2018-05-15
Project End
2023-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
4
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Neurosciences
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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