What causes build up of alpha-synuclein?

Exposure of neurons expressing endogenous levels of α-synuclein to fibrils causes formation of α-synuclein inclusions that morphologically and biochemically resemble Lewy neurites and Lewy bodies [15].

What is α-synuclein aggregation?

α-Synuclein is a protein that aggregates as amyloid fibrils in the brains of patients with Parkinson’s disease and dementia with Lewy bodies. Small oligomers of α-synuclein are neurotoxic and are thought to be closely associated with disease.

What causes misfolded alpha-synuclein?

The reason why alpha-synuclein becomes misfolded in the brain or the gut is unknown. We hypothesize that alpha-synuclein misfolding in gut and brain neurons in caused by exposure to proteins of similar structure that are contained in bacteria that reside in the mouth and gut.

How does alpha-synuclein spread?

Alpha-synuclein inclusions, the hallmarks of synucleinopathies, are suggested to spread along neuronal connections in a stereotypical pattern in the brains of patients. Ample evidence now supports that pathological forms of alpha-synuclein propagate in cell culture models and in vivo in a prion-like manner.

Where is alpha-synuclein found in the body?

Alpha-synuclein is abundant in the brain, and smaller amounts are found in the heart, muscles, and other tissues. In the brain, alpha-synuclein is found mainly at the tips of nerve cells (neurons) in specialized structures called presynaptic terminals.

What is the role of α-synuclein in the pathology of the disease?

Therefore, the main function of α-synuclein would appear to be the control of neurotransmitter release, through effects on the SNARE complex. Recent evidence, to be discussed below, suggests that this physiological function may provide insight into the aberrant function unleashed in disease states.

What are alpha-synuclein proteins?

Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. It is abundant in the brain, while smaller amounts are found in the heart, muscle and other tissues.

Why are some proteins more prone to aggregation?

It is well established that certain amino acids influence protein aggregation and that proteins with solvent exposed stretches of high hydrophobicity and a low net charge are aggregation-prone.

What are aggregation prone proteins?

Intracellular protein misfolding/aggregation are features of many late-onset neurodegenerative diseases, called proteinopathies. These include Alzheimer’s disease, Parkinson’s disease, tauopathies, and polyglutamine expansion diseases [e.g., Huntington’s disease; and various spinocerebellar ataxias (SCAs), like SCA3].

How does alpha synuclein cause Parkinson’s?

α-Synuclein may contribute to PD pathogenesis in a number of ways, but it is generally thought that its aberrant soluble oligomeric conformations, termed protofibrils, are the toxic species that mediate disruption of cellular homeostasis and neuronal death, through effects on various intracellular targets, including …

Is the endogenous α-synuclein protein self-propagating?

This hypothesis is based on discoveries that pathologic aggregates of α-synuclein induce the endogenous α-synuclein protein to adopt a similar pathologic conformation, and is thus self-propagating.

Where do α-synuclein aggregates appear in the brain?

Staging studies of Parkinson’s disease also support that α-synuclein aggregates appear in the brain in a temporally and spatially predictable manner [ 11, 12, 13 ]. In early stages, Lewy pathology first appears in the enteric nervous system and the olfactory bulb.

Which conformation of α-synuclein is responsible for neurodegenerative diseases?

Many proteins implicated in neurodegenerative diseases convert to a pathologic conformation that induces the endogenous protein to adopt the same conformation and is thus self-propagating [ 35 ]. It is critical to define the conformation of α-synuclein that is responsible for this pathogenic templating.

Do seeds of fibrillar α-synuclein induce normal α-synuclein to form pathogenic inclusions?

Multiple experimental studies have been published that support that seeds of fibrillar α-synuclein can induce normal α-synuclein to form pathogenic inclusions.