Templated α-Synuclein Inclusion Formation Is Independent of Endogenous Tau
Abstract
Synucleinopathies including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are characterized by neuronal intracellular inclusions of α-synuclein. PD dementia (PDD) and DLB are collectively the second most common cause of neurodegenerative dementia. In addition to associated inclusions, Lewy body diseases (LBDs) have dopaminergic neurodegeneration, motor defects and cognitive changes. The microtubule-associated protein tau has been implicated in LBDs, but the exact role of the protein and how it influences formation of α-synuclein inclusions is unknown. Reducing endogenous tau levels is protective in multiple models of Alzheimer’s disease (AD), tauopathies, and in some transgenic synucleinopathy mouse models. Recombinant α-synuclein and tau proteins interactin vitro. Here, we show tau and α-synuclein colocalize at excitatory presynaptic terminals. However, tau heterozygous and tau knock-out mice do not show a reduction in fibril-induced α-synuclein inclusions formation in primary cortical neurons, or after intrastriatal injections of fibrils at 1.5 month or six months later. At six months following intrastriatal injections, wild-type, tau heterozygous and tau knock-out mice showed a 50% reduction in dopamine neurons in the substantia nigra pars compacta (SNc) compared with mice injected with α-synuclein monomer, but there were no statistically significant differences across genotypes. These data suggest the role of tau in the pathogenesis of LBDs is distinct from AD, and Lewy pathology formation may be independent of endogenous tau.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 01, 2021
- Source ID
- 10.1523/eneuro.0458-20.2021
Entities
People
- Anna K. Cook
- Anner T. Harris
- Ashwin Narayanan
- Casey L. Mahoney-Crane
- David G. Standaert
- Drake R. Thrasher
- Dreson L. Russell
- Erik D. Roberson
- Laura A Volpicelli-Daley
- Lindsay E. Stoyka
- Tiara P. Janado
Organizations
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke
- United States Department of Defense