How can α-synuclein aggregation be prevented to slow progression of PD?

Prevention of or delaying the progression of Parkinson’s disease is the ultimate aim of many therapeutic strategies and targets include neuroinflammation, lysosomal dysfunction, iron overload, and aggregated α-synuclein. Strategies to prevent α-synuclein aggregation were highlighted at MDS Virtual Congress 2020.

Many symptoms of advanced PD are motor complications, including motor fluctuations and dyskinesias, and do not respond to dopaminergic medications,1 said Professor Tanya Simuni, Chicago, IL.

The ultimate goal of treatment is to prevent or delay progression

The ultimate goal of treatment is a disease-modifying therapy (DMT) that targets the underlying pathogenesis of PD to prevent or delay progression, but this is currently an unmet need, she explained.

However, the long prodromal period of PD, which can have a total duration of 20 years, provides an opportunity for DMT intervention,2 and many potential DMTs are under investigation.3

The long prodromal period provides an opportunity for DMT

Targets for these potential DMTs include neuroprotection and neuroinflammation, lysosomal dysfunction, iron overload, and α-synuclein.3

Why is α-synuclein a target?

Aggregated α-synuclein is the major constituent of the intraneuronal Lewy bodies associated with PD, dementia with Lewy bodies, and multiple system atrophy,4 said Professor Simuni; and the evidence suggests that α-synuclein and Lewy bodies play a role in PD pathogenesis:

  • Lewy bodies are first seen in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus and then propagate through the brain5
  • Lewy bodies appear in fetal neuron transplants in patients with PD, suggesting that α-synuclein might be transmitted using a prion-like mechanism6
  • misfolded α-synuclein can transfer between cells and act as a seed recruiting endogenous α-synuclein, leading to larger aggregates6

Preventing α-synuclein transfer from cell to cell might slow progression

Strategies that prevent α-synuclein transfer from cell to cell might therefore slow progression of symptoms in PD, said Professor Simuni.6

She added that the genetic landscape for PD includes α-synuclein gene mutations, providing further support for targeting α-synuclein as a target for DMT.7

Many classes of potential α-synuclein targeting DMTs are therefore now being investigated in clinical trials, concluded Professor Simuni, including active and passive immunotherapies and α-synuclein aggregation modulators and inhibitors.9

A satellite symposium sponsored by Roche.

 

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Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

References
  1. Hung AY, Schwartzchild MA. Neurotherapeutics. 2014;11:34–46.
  2. Hawkes CH, et al. Parkinsonism Relat Disord. 2010;16:79–84.
  3. Poewe W, et al. Neuropharmacol. 2020;171:108085.
  4. Goedert M, et al. Nat Rev Neurol. 2013;9:13–24.
  5. Braak H, et al. Neurobiol Aging. 2003;24:197–211.
  6. Angot E, et al. Lancet Neurol. 2010;9:1128–38.
  7. Polymeropoulos MH, et al. Science. 1997;276:2045–7.
  8. Wakabayashi K. Neuropathology. 2020;https://doi.org/10.1111/neup.12691.
  9. McFarthing K, et al. J Parkinsons Dis. 2020;10:757–74.
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