Editors' ChoiceNeurodegenerative Disease

Partners in crime: α-synuclein modulates pathologic tau spreading

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Science Translational Medicine  04 Nov 2020:
Vol. 12, Issue 568, eabf2645
DOI: 10.1126/scitranslmed.abf2645


Coadministration of fibrillar α-synuclein along with brain-derived tau seeds exacerbates tau spreading in mice.

Multiple neurodegenerative diseases including Alzheimer disease (AD), Parkinson disease (PD), and dementia with Lewy bodies are characterized by an overlapping pattern of insoluble protein aggregates including tau and α-synuclein (αSyn). Although in vitro and transgenic animal studies have suggested a cross-talk phenomenon whereby one protein modulates the aggregation of another, the relative influence of tau and αSyn on aggregation and spreading in injection models, which rely on endogenous protein expression, remains unclear. Now, Bassil et al. report that αSyn potentiates tau fibril–induced spreading of tau pathology but that tau does not substantially alter the pattern or rate of spreading of αSyn pathology.

Similar to prior studies, the authors induced seeding and spreading of αSyn pathology in wild-type mice by injecting preformed fibrils (PFFs) generated from recombinant αSyn. Whereas injecting sarkosyl-insoluble brain fractions enriched for pathological tau from patients with sporadic Alzheimer disease (AD-tau), the authors induced seeding and spreading of endogenous tau protein in wild-type mice. Notably, co-injection of αSyn PFFs with AD-tau accelerated the seeding and spreading of tau pathology in multiple brain regions, but the co-injection did not change the overall spreading pattern of αSyn pathology compared to αSyn PFF injection alone. Injection of αSyn PFFs induced similar spreading of αSyn pathology in both wild-type and tau knockout mice. On the contrary, in αSyn knockout mice, AD-tau injection resulted in reduced tau spreading in the short term (3 to 6 months) but increased spreading at later time points (9 months), compared to wild-type mice. This reversal in the pattern of tau pathology burden in αSyn knockout mice over time is curious and warrants further investigation to determine whether compensatory changes occur with aging in the context of protein aggregation or neurodegeneration. Finally, the authors also found a positive correlation between tau and αSyn pathology in the brainstem but not in the hippocampus or entorhinal cortex in patients with PD.

Although these results indicate that αSyn plays a pivotal role in modulating pathologic tau spreading, which may have important implications for disease-modifying therapies for multiple neurodegenerative disorders, additional studies are needed to determine the functional implications of protein cross-seeding on neuronal physiology and the consequences of specific protein–targeted interventions on cognitive and motor impairment.

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