Alpha-synuclein and tau: teammates in neurodegeneration?

Abstract

The accumulation of α-synuclein aggregates is the hallmark of Parkinson’s disease, and more generally of synucleinopathies. The accumulation of tau aggregates however is classically found in the brains of patients with dementia, and this type of neuropathological feature specifically defines the tauopathies. Nevertheless, in numerous cases α-synuclein positive inclusions are also described in tauopathies and vice versa, suggesting a co-existence or crosstalk of these proteinopathies. Interestingly, α-synuclein and tau share striking common characteristics suggesting that they may work in concord. Tau and α-synuclein are both partially unfolded proteins that can form toxic oligomers and abnormal intracellular aggregates under pathological conditions. Furthermore, mutations in either are responsible for severe dominant familial neurodegeneration. Moreover, tau and α-synuclein appear to promote the fibrillization and solubility of each other in vitro and in vivo. This suggests that interactions between tau and α-synuclein form a deleterious feed-forward loop essential for the development and spreading of neurodegeneration. Here, we review the recent literature with respect to elucidating the possible links between α-synuclein and tau.

Cortical Thinning Associated with Age and CSF Biomarkers in Early Parkinson’s Disease Is Modified by the SNCA rs356181 Polymorphism

“…The fact that there exists a significant interaction between α-synuclein and tau proteins at the molecular level [15], which was also found to be modulated by SNCA polymorphisms [16], provides biological support for our hypothesis that these polymorphisms may alter the neural damage exerted by both biomarkers.…”

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…Remarkably, there is also evidence that these various protein aggregates can interact with each other [29]. For example, Aβ promotes the aggregation of α-syn and tau in AD and DLB [30,31], α-syn and tau interact in the brain of patients with PD and DLB [32,33], α-syn and Aβ can form hetero-oligomers [34,35], and α-syn can modulate the fibrillization state of Aβ [36].…”

Metabolic Topology of Neurodegenerative Disorders: Influence of Cognitive and Motor Deficits

“…Although pathophysiologically and clinically different, PD and AD share some aspects in common: both are age-related neurodegenerative disorders characterized by aggregation of pathologic proteins leading to dysfunction of cerebral networks and distinct patterns of metabolic changes (3)(4)(5)(6). Cases characterized by pure PD (a-synuclein aggregation) or pure AD (amyloid and tau aggregation) pathology do not represent most affected patients.…”

“…Biologically and histopathologically, there is an overlap of these age-associated proteinopathies. They form a continuum with concomitant amyloid-, tau-, and a-synuclein aggregation as well as microvascular changes (6,7).…”