α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes

Abstract

The accumulation of α-synuclein (α-syn) aggregates in specific brain regions is a hallmark of synucleinopathies including Parkinson disease (PD). α-Syn aggregates propagate in a “prion-like” manner and can be transferred inside lysosomes to recipient cells through tunneling nanotubes (TNTs). However, how lysosomes participate in the spreading of α-syn aggregates is unclear. Here, by using super-resolution (SR) and electron microscopy (EM), we find that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. In addition, we demonstrate that α-syn fibrils induce peripheral redistribution of lysosomes, likely mediated by transcription factor EB (TFEB), increasing the efficiency of α-syn fibrils’ transfer to neighboring cells. We also show that lysosomal membrane permeabilization (LMP) allows the seeding of soluble α-syn in cells that have taken up α-syn fibrils from the culture medium, and, more importantly, in healthy cells in coculture, following lysosome-mediated transfer of the fibrils. Moreover, we demonstrate that seeding occurs mainly at lysosomes in both donor and acceptor cells, after uptake of α-syn fibrils from the medium and following their transfer, respectively. Finally, by using a heterotypic coculture system, we determine the origin and nature of the lysosomes transferred between cells, and we show that donor cells bearing α-syn fibrils transfer damaged lysosomes to acceptor cells, while also receiving healthy lysosomes from them. These findings thus contribute to the elucidation of the mechanism by which α-syn fibrils spread through TNTs, while also revealing the crucial role of lysosomes, working as a Trojan horse for both seeding and propagation of disease pathology.

Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models

“…However, it might also be possible that divergent subcellular localization of SNCA conformers explains their different susceptibility toward CTSD degradation. Although all SNCA forms reach the lysosome for degradation [ 24 , 26 ], high molecular weight forms of SNCA have been shown to leak [ 97 ], hence potentially escaping the rescue strategy by CTSD treatment. This might also be the case for other CTSD substrates, like the PRNP that has also been shown to escape lysosomal structures [ 98 ].…”

Effects of oligomer toxicity, fibril toxicity and fibril spreading in synucleinopathies

“…Accordingly, lysosomal impairment was described to increase αSyn transfer between cells [194]. Recently, the mechanism by which αSyn fibrils spread through lysosomes was described in more detail: they were reported to alter lysosomal morphology and functionality, and to induce the peripheral redistribution of lysosomes, thus increasing their transfer to neighboring cells [195]. The transmission of αSyn fibrils through TNTs was also observed by Dieriks and collaborators in SH-SY5Y cells and in primary human brain pericytes derived from postmortem PD brains, pointing out the central role of non-neuronal cells in PD progression [196].…”

SARS-CoV-2: A Master of Immune Evasion

“…TNTs are defined as transitory formations that emerge and dissolve in a few minutes [ 128 ]. Viruses [ 129 , 130 , 131 ], prions [ 132 ] and other neurodegeneration-related prion-like proteins [ 133 , 134 , 135 ], such as tau [ 135 , 136 ], α-synuclein [ 137 , 138 , 139 ] and amyloid-β [ 140 ], as well as fungi [ 141 ] and mycoplasma [ 142 ] have all been found to help spread corresponding diseases using nanotubes.…”