Alpha-synuclein, a key player in Parkinson's disease and dementia and its new presentations in tissue.

Parkinson’s disease (PD) belongs the group of neurodegenerative synucleinopathies characterized by progressive aggregation of the neuronal protein alpha-synuclein (asyn) and spreading of such aggregates in the nervous system. 

The symptomatology of synucleinopathies is characterized by both motor and non-motor symptoms and reflects that both the central and peripheral nervous systems are affected.

Histopathological diagnosis has hitherto been defined by loss of pigmented neurons in the locus coeruleus producing noradrenaline and dopamine in substantia nigra pars compacta, and by the presence of so-called Lewy pathology in affected areas consisting of Lewy bodies in the soma of neurons and Lewy neurites in axons. This Lewy pathology  is detectable by antibodies toward asyn. 

Recent immunohistochemical analyses based on proximity ligation assay techniques have revealed a wider presence of asyn aggregates than what is appreciated by the distribution of Lewy pathology and can even be detected in cases with no detectable Lewy bodies. 

The nature of such asyn aggregates is unknown but could be related the asyn seeds present in CSF of pre-diagnostic cases that currently are detected by seed amplification asays.

The presentation will describe recent and novel findings on asyn aggregates in brain tissue and present a framework for how we may consider the nature and pathophysiological effects of such wide-spread aggregates. 
 

Learning Objectives:

1. Describe the role of alpha-synuclein aggregation and spreading in the pathophysiology of Parkinson’s disease and related synucleinopathies.

2. Distinguish between classical Lewy pathology and newly identified alpha-synuclein aggregates detected by proximity ligation assay techniques.

3.