Alpha-Synuclein on Trial

“Lewy body pathology antidates clinical Parkinsonism,” Stefanis said.

He also highlighted newer evidence suggesting that classical Lewy bodies may represent only the visible tip of a much larger pathological iceberg. Recent studies using advanced imaging and antibody techniques have identified oligomeric alpha-synuclein species and extensive synaptic pathology even before overt Lewy body formation.

“This hidden pathology has been uncovered more recently,” he said.

One of Stefanis’ strongest arguments involved the new generation of seed amplification assays, which can detect pathological alpha-synuclein in cerebrospinal fluid, skin biopsies and potentially blood samples. These assays are increasingly able to identify abnormal alpha-synuclein years before classical Parkinson’s symptoms emerge.

“It’s something that occurs early,” Stefanis said, arguing that the biomarker evidence had “cemented this neuropathological notion that alpha-synuclein pathology comes before and correlates with disease manifestations.”

Perhaps most importantly, Stefanis did not present Parkinson’s as a single disease beginning in a single way. Mitochondrial dysfunction, lysosomal failure, inflammation and environmental factors may all contribute, he argued. But many of these pathways appear to funnel into pathological alpha-synuclein biology, which then becomes self-propagating.

“There are other factors,” he said, “but they really have to funnel into this main driver of pathology, which is pathological alpha-synuclein.”

In that formulation, alpha-synuclein is not necessarily the spark. It is the engine.

The defence responds

Barker’s strategy was different. Rather than denying the importance of alpha-synuclein, he attacked the idea that it occupies a uniquely privileged position in Parkinson’s disease.

His critique began with genetics. Yes, SNCA mutations exist, he acknowledged. But they account for only a tiny fraction of Parkinson’s cases.

“These account for 0.1 per cent of people with Parkinson’s,” Barker said. “So we can ignore those.”

Genome-wide association studies implicate many genes, he argued, not just alpha-synuclein. And in some populations, alpha-synuclein does not even emerge strongly in the data.

“So it clearly can’t be the central piece of the puzzle,” Barker said.

But Barker’s deeper challenge concerned causation itself. Parkinsonism can occur without classical Lewy pathology. Conversely, substantial alpha-synuclein pathology can exist in individuals without clinical Parkinson’s disease.

“We have a beautiful double dissociation,” Barker said. “Parkinsonism can be found without alpha-synuclein, and alpha-synuclein pathology can be found without Parkinson’s.”

The point cut directly at the conceptual core of the alpha-synuclein hypothesis. A pathological hallmark is not necessarily the same thing as a disease driver.

Barker repeatedly returned to what he views as a cautionary precedent: Alzheimer’s disease. For decades, Alzheimer’s research focused intensely on beta-amyloid. The logic seemed overwhelming — strong genetics, overwhelming pathology, clear biomarker signals. Yet despite enormous effort, therapies removing amyloid have yielded only limited clinical benefit.

“We target that protein. Makes no difference,” Barker said, referring first to Huntington’s disease and then drawing parallels to Alzheimer’s and Parkinson’s.

That therapeutic disappointment hangs heavily over the entire Parkinson’s field. Multiple anti-alpha-synuclein antibody trials have failed to produce convincing disease-modifying results.

“If you try and target alpha-synuclein,” Barker said, “nobody seems to get better.”

Supporters of the alpha-synuclein hypothesis argue interventions may simply be arriving too late, after pathology has already spread widely through neural systems. Critics counter that the failures expose a deeper problem with the theory itself.

A field between paradigms

What emerged in Phoenix was not simply disagreement over one protein, but evidence of a discipline caught between competing models of disease.

One model — represented broadly by Stefanis — sees Parkinson’s as fundamentally organised around pathological alpha-synuclein biology. The other — articulated by Barker — sees Parkinson’s as a far more heterogeneous systems disorder involving multiple interacting pathologies and vulnerabilities.

Increasingly, the field appears to occupy an uneasy middle ground between those positions.

Few researchers now deny alpha-synuclein’s importance. The evidence tying the protein to Parkinson’s pathology is too extensive. Yet confidence in single-protein explanations has weakened. The failure of disease-modifying therapies, combined with growing recognition of biological heterogeneity, has pushed many researchers toward more pluralistic models involving aging, immunity, metabolism, vascular biology, mitochondrial dysfunction, lysosomal stress and gut-brain interactions.

In that emerging framework, alpha-synuclein may still matter profoundly. Just perhaps not alone.

The unresolved verdict

As the debate closed, the courtroom imagery remained strangely apt. Stefanis had presented alpha-synuclein as the prime suspect in Parkinson’s disease — present early, biologically capable and increasingly detectable before symptoms emerge. Barker had argued that the case remained largely circumstantial.

“Alpha-synuclein,” Barker concluded, “whilst being on the scene of the crime, is not the only one who is there.”

Both men are respected scientists. Both are colleagues. Both clearly enjoyed the theatricality of the exchange. But beneath the humour sat a reality neither side disputed: Parkinson’s disease remains unsolved.