Alpha-synuclein Clumps, Tau Tangles May Have Distinct Roles

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by Steve Bryson PhD |

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alpha-synuclein, tau

The formation of toxic clumps of the protein alpha-synuclein, a hallmark of Parkinson’s disease, was not affected by reducing levels of tau, a protein that also forms aggregates in both Parkinson’s and Alzheimer’s disease, a mouse study suggested.

These results imply that the role of tau in Parkinson’s is distinct from Alzheimer’s, where lowering tau tangles — aggregates, or clumps of that protein — has been suggested as a possible therapeutic approach, the scientists said.

The study, “Templated α-Synuclein Inclusion Formation Is Independent of Endogenous Tau,” was published in the journal eNeuro.

Parkinson’s disease is characterized by the clumping (aggregation) of misfolded alpha-synuclein protein in brain cells (neurons), which leads to a loss of neurons that produce dopamine, a chemical messenger involved in controlling motor function.

Toxic alpha-synuclein aggregation can affect regions of the brain essential to cognitive function, causing dementia. These toxic clumps form structures called Lewy bodies and are the underlying cause of Lewy body dementia (LBD).

Parkinson’s also is associated with variants of the MPAT gene, which carries instructions for the tau protein. Tau can form toxic aggregates — or tau tangles — which is one of the hallmarks of Alzheimer’s.

The presence of toxic aggregates of these two proteins strongly correlates with cognitive decline in Parkinson’s dementia. Some studies even suggest that an interaction of alpha-synuclein and tau may contribute to the development of Parkinson’s.

Although reducing tau levels is protective in models of Alzheimer’s disease, studies in Parkinson’s models have generated mixed results. Thus, further characterization of alpha-synuclein and tau in Lewy body formation in Parkinson’s is needed.

Now, Laura A. Volpicelli-Daley, PhD, led a team of researchers at the University of Alabama at Birmingham in investigating whether reducing tau influenced the formation of alpha-synuclein aggregation in mouse neurons.

Mice were bred that lacked one or both copies of the MPAT gene (one from each parent). Mice with one copy retained about 50% of tau, which mimicked a therapeutically induced reduction.

An initial set of experiments showed that, in neurons cultured from these mice and healthy mice as a control, alpha-synuclein and tau were found to interact. Further examination of mice brain tissue found both proteins located close to synapses, the place where neurons connect.

To examine the impact of reduced tau on alpha-synuclein aggregate formation, an altered form of alpha-synuclein — one more prone to form Lewy bodies — was added to neurons from normal and tau-deficient mice. The nerve cells were found to take up some altered protein, which acted as a seed to attract normal alpha-synuclein. That, in turn, resulted in further disease-causing clumps that impaired neuron function, similar to what is found in Parkinson’s patients.

Compared with normal mice, the abundance of alpha-synuclein aggregates was not decreased in neurons from mice with reduced tau or those without tau.

An additional experiment confirmed that reducing or removing tau did not influence the natural (endogenous) production of alpha-synuclein in four brain regions, including the midbrain, hippocampus, cortex, or striatum.

To learn more, the mouse models next were injected with altered alpha-synuclein seeds at 3-4 months of age. The scientists then analyzed their brain tissue at 6-7 months. Regardless of the presence, reduction, or absence of tau, the abundance of alpha-synuclein aggregates was the same in all brain regions examined.

Dopamine-producing neurons are part of a region in the midbrain called the substantia nigra. A detailed examination of this region at six to seven months after injection with altered alpha-synuclein found, as expected, about a 50% loss of dopamine-producing neurons compared with control mice. However, no differences were seen in healthy or tau-deficient mice.

An earlier, six-week time-point was assessed, as the researchers hypothesized that potential differences in the abundance of alpha-synuclein clumps may be minimal at six months. Again, robust formation of aggregates was seen 1.5 months after injection, and there were no significant differences between normal mice or those with reduced tau.

Final experiments looked for behavioral changes due to alpha-synuclein and tau, or just tau alone. An open field test showed mice with partial tau, six months after injection, walked a shorter distance than normal mice given altered protein. Beyond this outcome, there were no significant differences in average velocity or time in the center, which measures anxiety. Additionally, no differences in any test were found six weeks after infection.

“Overall, our results indicate that endogenous tau does not play a role in seeded [alpha-synuclein aggregate] formation,” the researchers wrote. “However, because tau pathology [disease] is present in a subset of patients with [Parkinson’s disease], it is possible that abnormal tau assemblies are playing a role in [Parkinson’s] phenotypes [characteristics].”

“Additional studies are needed to further explore the therapeutic benefit of tau reduction in LBDs, but these results suggest that Lewy-like pathology is independent of tau,” they added.

Volpicelli-Daley, an associate professor of neurology, said lowering tau tangles may not by itself be a potential treatment.

“Here, we have shown that reduction of endogenous tau did not influence formation of templated alpha-synuclein inclusion formation or the loss of dopamine neurons,” Volpicelli-Daley said in a press release. “This suggests that therapeutics directed to tau for Parkinson’s disease may be more complicated than tau reduction. This is unlike Alzheimer’s disease, where tau reduction has been suggested as a possible therapy.”