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Spillantini Lab

 

Alpha synuclein

α-Synucleinopathies are a group of  neurodegenerative disorders characterised by the formation of intracellular clumps of α-synuclein in very specific neuronal and non-neuronal cells. The neurons are important for the initiation and control of volontary movement like walking, so the death of these neurons leads to the clinical signs. These diseases are typically movement disorders with or without dementia such as Parkinson's, Dementia with Lewy bodies (DLB), and Multiple system atrophy.

Parkinson's disease patients have characteristic motor features such as resting tremor, rigidity, bradykinesia (reduced movement), postural instability, flexed posture and freezing. Patients can additionally exhibit secondary motor symptoms and non-motor symptoms such as autonomic dysfunction (e.g. constipation), cognitive and psychiatric abnormalities, sleep disorders and sensory problems.

The core features of DLB besides parkinsonism include cognitive impairment, fluctuating cognition and recurrent visual hallucinations. MSA patients typically suffer from a variable combination of extrapyramidal symptoms, cerebellar ataxia and autonomic dysfunction.

In adults, α-synuclein is mainly found in neuronal presynaptic terminals and blood cells. Synapses are gaps between neurons in which the signal jumps via chemicals called neurotransmitters. In neurons α-synuclein is thought to be involved in moving packages of neurotransmitter to the presynaptic membrane for release into the synapse. This allows the neuronal signal to transmit from one neuron to the next. However, in disease it fails to do this, reducing the transmission across neurons in the motor networks, and even taking on a new toxic role.

Emerging evidence suggests that pathological α-synuclein behaves like a prion, a proteinaceous infectious particle capable of forming toxic aggregates and templating the misfolding of naive protein. Studies have reported that α-synuclein spreads in a prion-like fashion, being transmitted from diseased to healthy neurons, where it recruits and induces the aggregation of new α-synuclein. Current research also explores whether α-synuclein ‘strains’ exist. For example α-synuclein mis-folded in one way is different from α-synuclein mis-folded in another. These different 'stains' could explain why the same protein (α-synuclein) can aggregate and give rise to different diseases.

Ongoing research in the lab aims to isolate specific α-synuclein strains and propagate them from neuron to neuron in a dish to determine which are most toxic and which produce aggregates that best mimic those seen in the disease.  

 

Spreading of pathology

α-Synuclein transmission could potentially underlie pathological progression in α-synucleinopathies. Extensive research suggests that α-syn can be transferred from diseased to healthy neurons. For instance, α-synuclein transfer from host cells into grafted mouse cortical neuronal stem cells in mice expressing human α-synuclein.

Some groups propose the spreading is via the synapse, for example, in Luk et al.’s (2012) model, pathology progresses along regions synaptically connected to the injection site, whist non-innervated regions remain spared. To investigate this, the Spillantini lab is making models of α-Synuclein spreading with cells grown in a dish to study the mechanism and how it might be stopped.

 

Drug screening

The Spillantini lab has several drug screening platforms and collaborates with industry giants to test libraries of chemicals. These platforms range from the molecular, such as protein misfolding cyclic amplification (PMCA), to human neurons grown from iPSCs, to transgenic animals.