Alpha synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome

Abstract

Protein aggregates are the pathogenic hallmarks of many different neurodegenerative diseases and include the accumulation of α-synuclein, the main component of Lewy bodies found in Parkinson's disease. Aggresomes are closely-related, cellular accumulations of misfolded proteins. They develop in a juxtanuclear position, adjacent to the centrosome, the microtubule organizing centre of the cell, and share some protein components. Despite the long-standing observation that aggresomes/Lewy bodies and the centrosome sit side-by-side in the cell, no studies have been done to see whether these protein accumulations impede organelle function. We investigated whether the formation of aggresomes affected key centrosome functions: its ability to organize the microtubule network and to promote cilia formation. We find that when aggresomes are present, neuronal cells are unable to organise their microtubule network. New microtubules are not nucleated and extended, and the cells fail to respond to polarity cues. Since neurons are polarised, ensuring correct localisation of organelles and the effective intracellular transport of neurotransmitter vesicles, loss of centrosome activity could contribute to functional deficits and neuronal cell death in Parkinson's disease. In addition, we provide evidence that many cell types, including dopaminergic neurons, cannot form cilia when aggresomes are present, which would affect their ability to receive extracellular signals.

Ciliogenesis is Not Directly Regulated by LRRK2 Kinase Activity in Neurons

“…Taken together, we observed no negative effect of LRRK2 kinase activity on ciliogenesis in neurons but an increase in ciliogenesis in the G2019S fibroblast cell line, opposite to many previous reports [ 11 , 14 - 18 , 39 ]. Our data recommend a careful approach to investigating the relationship between LRRK2 kinase activity and ciliogenesis and suggest that the genetic background must be considered to explain the relationship between LRRK2 kinase activity and ciliogenesis.…”

Primary Cilia in Glial Cells: An Oasis in the Journey to Overcoming Neurodegenerative Diseases

“…• Decrease of the PSA-NCAM complex causes aggregation of α-synuclein, leading to Lewy body pathology Han et al, 2008;Iqbal et al, 2020;Matsumoto et al, 2019;Papastefanaki et al, 2007;Sorrentino et al, 2019 increasing neurotoxicity via secretion of inflammatory cytokines under activation of Aβ (De Strooper and Karran, 2016;Liao et al, 2016;Keren-Shaul et al, 2017). Notably, increased Aβ deposition affects the assembly and length control of primary cilia in astrocytes, thereby inhibiting the activation of the Shh signaling pathway and eventually disrupting neuronal survival (Vorobyeva and Saunders, 2018).…”

Insulin-degrading enzyme ablation in mouse pancreatic alpha cells triggers cell proliferation, hyperplasia and glucagon secretion dysregulation

“…In searching for a mechanism to explain the increased alpha cell proliferation and the perturbation in stimulated release of glucagon and insulin, we elected to focus on αsynuclein, a small, aggregation-prone protein that has been shown to regulate the cytoskeleton in several secretory cell types, including neurons and endocrine cells [18]. IDE regulates intracellular levels of α-synuclein as well as its aggregation by a non-proteolytic interaction wherein α-synuclein monomers bind essentially irreversibly to IDE.…”