Reducing INS-IGF1 signaling protects against non-cell autonomous vesicle rupture caused by SNCA spreading.

ABSTRACT

Aging is associated with a gradual decline of cellular proteostasis, giving rise to devastating protein misfolding diseases, such as Alzheimer disease (AD) or Parkinson disease (PD). These diseases often exhibit a complex pathology involving non-cell autonomous proteotoxic effects, which are still poorly understood. Using Caenorhabditis elegans we investigated how local protein misfolding is affecting neighboring cells and tissues showing that misfolded PD-associated SNCA/α-synuclein is accumulating in highly dynamic endo-lysosomal vesicles. Irrespective of whether being expressed in muscle cells or dopaminergic neurons, accumulated proteins were transmitted into the hypodermis with increasing age, indicating that epithelial cells might play a role in remote degradation when the local endo-lysosomal degradation capacity is overloaded. Cell biological and genetic approaches revealed that inter-tissue dissemination of SNCA was regulated by endo- and exocytosis (neuron/muscle to hypodermis) and basement membrane remodeling (muscle to hypodermis). Transferred SNCA conformers were, however, inefficiently cleared and induced endo-lysosomal membrane permeabilization. Remarkably, reducing INS (insulin)-IGF1 (insulin-like growth factor 1) signaling provided protection by maintaining endo-lysosomal integrity. This study suggests that the degradation of lysosomal substrates is coordinated across different tissues in metazoan organisms. Because the chronic dissemination of poorly degradable disease proteins into neighboring tissues exerts a non-cell autonomous toxicity, this implies that restoring endo-lysosomal function not only in cells with pathological inclusions, but also in apparently unaffected cell types might help to halt disease progression.Abbreviations AD Alzheimer disease; BM basement membrane; BWM body wall muscle; CEP cephalic sensilla; CLEM correlative light and electron microscopy; CTNS-1 cystinosin (lysosomal protein) homolog; DA dopaminergic; DAF-2 abnormal dauer formation; ECM extracellular matrix; FLIM fluorescence lifetime imaging microscopy; fps frames per second; GFP green fluorescent protein; HPF high pressure freezing; IGF1 insulin-like growth factor 1; INS insulin; KD knockdown; LMP lysosomal membrane permeabilization; MVB multivesicular body; NOC nocodazole; PD Parkinson disease; RFP red fluorescent protein; RNAi RNA interference; sfGFP superfolder GFP; SNCA synuclein alpha; TEM transmission electron microscopy; TNTs tunneling nanotubes; TCSPC time correlated single photon counting; YFP yellow fluorescent protein.