Zane Jaunmuktane, United Kingdom

Division of Neuropathology National Hospital for Neurology and Neurosurgery

Author Of 1 Presentation

 Conference Calendar

BRAIN REGION SPECIFIC PATHOLOGY SPREAD IN SPORADIC PARKINSON’S DISEASE AND DEMENTIA WITH LEWY BODIES IS GOVERNED BY Α-SYNUCLEIN CONFORMATIONS.

Session Name
DISEASE MECHANISMS, PATHOPHYSIOLOGY, LARKK.2 PARKIN. ALPHA -SYNUCLEIN
Session Type
SYMPOSIUM
Date
14.03.2021, Sunday
Session Time
10:00 - 12:00
Room
On Demand Symposia C
Lecture Time
10:45 - 11:00
Presenter
Session Icon
On-Demand

Abstract

Aims

The α-synuclein (αSYN) protein is encoded by the SNCA gene and is thought to be a driver in the pathogenic mechanism of the two neurodegenerative diseases Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). What underlies the differences in region specific dysfunction in both diseases is still unclear. The αSYN protein exists in different physiological conformations: the cytosolic, active but susceptible (aggregation-prone) monomer (αSYNCS), and higher-order, cytosolic protective (aggregations-resistant) multimers (αSYNCP). It has been shown that SNCA mutations associated with familial PD destabilize the equilibrium of αSYNCS/ αSYNCP and that relative increase of the aggregation-prone monomer is causal for the neurodegeneration in model systems.

Methods

Here, we characterized the balance and levels of αSYNCS and αSYNCP in post-mortem native human brain tissue from sporadic PD and DLB patients in different brain regions according to the spreading theory of αSYN and classical Braak staging system.

Results

We show that the equilibrium of αSYNCS/ αSYNCP is destabilized in sporadic PD and DLB patients resulting in brain region-specific alterations according to the spread of Lewy body pathology, implying the αSYNCS/ αSYNCP equilibrium as an determining factor of temporal and spatial disease progression. Moreover, demented PD and DLB patients exhibited a specific decrease of the αSYNCS/ αSYNCP equilibrium in neocortical regions, implying that the region specific decrease is important for the dementia component of synculeinopathies.

Conclusions

Thus, our data suggest an association of αSYNCS/ αSYNCP destabilization in sporadic synucleinopathies related to the spreading of αSYN pathology and subsequently different (clinical) manifestations of neurodegeneration.

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