Chittoor-Vinod, V. G. | bioRxiv Science

bioRxiv2026

Cryo-EM Structures of Infectious Low-Twist α-Synuclein Filaments in Lewy Bodies

-Synuclein (aSyn) aggregation within Lewy bodies underlies Parkinson's disease and associated dementias. These aggregates are often comprised of amyloid filaments, most of which appear untwisted or have extremely low twist, complicating high-resolution structural determination by cryogenic electron microscopy (cryo-EM). Here, we isolated filaments from the brain tissue of a patient with dementia with Lewy bodies and show infectivity in a cell line system that propagates Lewy aSyn. Then, we determined 2.3-2.9 [A] cryo-EM structures of low-twist aSyn filaments from this tissue and from a publicly available Parkinson's disease dementia dataset. In both structures, the protofilament adopts a fold highly similar to the canonical Lewy fold with conserved cofactor and peptidic densities. Compared to previously resolved high-twist filaments, the low-twist filament is left-handed and flattened along the filament axis, resulting in register shifts of interlayer contacts, while preserving the overall architecture. Our results establish that low-twist filaments, which include over 75% of disease-associated Lewy aSyn amyloids, share a common structural core with high-twist forms and are the predominant aSyn species in samples that engage in templated infection.

biophysics↗

bioRxiv2020

Dietary Amino Acids Impact LRRK2-induced Neurodegeneration in Parkinson's Disease Models

The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of Parkinsons disease (PD) and results in age-related dopamine neuron loss and locomotor dysfunction in Drosophila melanogaster through an aberrant increase in bulk neuronal protein synthesis. Under non-pathologic conditions, protein synthesis is tightly controlled by metabolic regulation. Whether nutritional and metabolic influences on protein synthesis can modulate the pathogenic effect of LRRK2 on protein synthesis and thereby impact neuronal loss is a key unresolved question. Here, we show that LRRK2 G2019S-induced neurodegeneration is critically dependent on dietary amino acid content. Low dietary amino acid concentration prevents aberrant protein synthesis and blocks LRRK2 G2019S-mediated neurodegeneration in Drosophila and rat primary neurons. Unexpectedly, a moderately high amino acid diet also blocks dopamine neuron loss and motor deficits in Drosophila through a separate mechanism involving stress-responsive activation of 5-AMP-activated protein kinase (AMPK) and neuroprotective induction of autophagy, implicating the importance of protein homeostasis to neuronal viability. At the highest amino acid diet of the range tested, PD-related neurodegeneration occurs in an age-related manner, but is also observed in control strains, suggesting that it is independent of mutant LRRK2 expression. We propose that dietary influences on protein synthesis and autophagy are critical determinants of LRRK2 neurodegeneration, opening up possibilities for future therapeutic intervention.

neuroscience↗