Synucleinopathy

Original Editor - Lucinda hampton

Top Contributors - Lucinda hampton, Uchechukwu Chukwuemeka, Kim Jackson and Angeliki Chorti  

Introduction

α-syn, a protein in the brain

Synucleinopathies are a subgroup of neurodegenerative diseases, characterised by impairment of alpha-synuclein (αSyn) metabolism, producing abnormal intracellular deposits (namely progressive aggregation of insoluble fibrillary αSyn in neurons and glia). All of them are chronic, progressive disorders that lack a causal therapy.

Although the exact mechanism of initiation of aggregation and misfolding pathway of a-Syn is yet to be discovered; it’s mechanism of spreading through interconnected neuronal networks is a proposed theory. This theory suggests that a-Syn released from the diseased cell and is then uptaken by normal adjacent cells.

Divisions Of Synucleinopathies

The synucleinopathies can be divided into those with and those without the formation of Lewy bodies (however some overlap does exist) and include:

1. Synucleinopathies with Lewy bodies: Parkinson disease (PD); Lewy body disease (LBD);
2. Synucleinopathies without Lewy bodies: Multiple systemic atrophy (MSA); pure autonomic failure; rapid eye movement (REM) sleep behaviour disorder.

This 4 minute video gives a introduction to the synucleinopathies

Human Alpha-Synuclein (α-syn)

Human alpha-synuclein (α-syn) is predominantly expressed in the brain, accounting for approximately 1% of brain weight. It is found chiefly in the neocortex, hippocampus, substantia nigra, thalamus, and cerebellum, and is found in Lewy bodies (LBs). As well as accumulating in the brain, α-synuclein also accumulates in the gastrointestinal tract resulting in symptoms.

Main Symptoms

Certain brain regions light up during normal cognitive functions

Synucleinopathies are chronic disorders that develop gradually. Symptoms include:

1. A decline in motor and cognitive functions
2. Behavioral changes.

Symptoms of these diseases significantly overlap with one another, hindering diagnosis. for example parkinsonism is the predominant symptom of PD, but it can be indistinguishable from the parkinsonism of LBD and MSA.

Future Management

Protein folding figure

In healthy brain cells, correctly constructed alpha synuclein is typically found just inside the surface of the membrane surrounding the cell body and in the presynaptic terminals (critical to passing messages between neurons).

The abnormal aggregation of α-synuclein has proved to be the “rosetta stone” of PD, DLB and MSA. There is increasing evidence demonstrating the propagation of pathological α-Syn to be central to the pathogenesis of synucleinopathies, for example in PD and MAS.

Comprehending disease aetiology and pathogenesis is a start, but developing safe and effective mechanism-based treatments is the goal. For example, some pharmaceutical companies are focusing on compounds that prevent α-syn from aggregation. When mechanism-based therapies for PD, LBD, and MSA will become available, they will probably interfere with the neurodegeneration caused by the aggregation of α-synuclein.