Abstract
Accumulation of pathological α-synuclein aggregates plays a major role in Parkinson’s disease. Macroautophagy is a mechanism to degrade intracellular protein aggregates by wrapping them into autophagosomes, followed by fusion with lysosomes. We had previously shown that pharmacological activation of macroautophagy protects against α-synuclein-induced toxicity in human neurons. Here, we hypothesized that inhibition of macroautophagy would aggravate α-synuclein-induced cell death.Unexpectedly, inhibition of autophagosome formation by silencing of ATG5 protected from α-synuclein-induced toxicity. Therefore, we studied alternative cellular mechanisms to compensate for the loss of macroautophagy. ATG5 silencing did not affect the ubiquitin–proteasome system, chaperone systems, chaperone-mediated autophagy, or the unfolded protein response. However, ATG5 silencing increased the secretion of α-synuclein via exosomes. Blocking exosomal secretion exacerbated α-synuclein-induced cell death.We conclude that exosomal secretion of α-synuclein is increased after impaired formation of autophagosomes to reduce the intracellular α-synuclein burden. This compensatory mechanism prevents α-synuclein-induced neuronal cell death.
Highlights
Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the accumulation of the protein α-synuclein (α-Syn) in Lewy bodies or Lewy neurites in vulnerable neurons1–3. α-Syn is a small presynaptic protein which consists of three domains
In cells treated with chloroquine, autophagy-related gene 5 (ATG5) small interfering RNAs (siRNA) reduced LC3B-II levels (p < 0.001), demonstrating that ATG5 silencing reduced the generation of autophagosomes in Lund human mesencephalic (LUHMES) neurons
We found that inhibition of autophagy by silencing of ATG5 protected LUHMES neurons from α-Syn-induced toxicity
Summary
Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the accumulation of the protein α-synuclein (α-Syn) in Lewy bodies or Lewy neurites in vulnerable neurons1–3. α-Syn is a small presynaptic protein which consists of three domains. Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the accumulation of the protein α-synuclein (α-Syn) in Lewy bodies or Lewy neurites in vulnerable neurons. Α-Syn is a small presynaptic protein which consists of three domains. Point mutations (e.g. A30P, G51D, A53E, A53T, E46K) of SNCA, the gene encoding α-Syn lead to autosomal-dominant PD6. Duplications and triplications of wildtype SNCA cause autosomal-dominant PD7,8. Monogenic forms of PD are rare and most cases are sporadic[9,10]. Genome-wide association studies consistently found single nucleotide polymorphisms in SNCA as major risk factors for sporadic PD11–13. Α-Syn can be degraded by various intracellular protein degradation mechanisms, including the ubiquitin–proteasome system (UPS)[14], chaperone-mediated autophagy (CMA)[15], or macroautophagy[14] Genome-wide association studies consistently found single nucleotide polymorphisms in SNCA as major risk factors for sporadic PD11–13. α-Syn can be degraded by various intracellular protein degradation mechanisms, including the ubiquitin–proteasome system (UPS)[14], chaperone-mediated autophagy (CMA)[15], or macroautophagy[14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
