α-Synuclein: Multiple pathogenic roles in trafficking and proteostasis pathways in Parkinson’s disease

Annie J. Zalon, Drew J. Quiriconi, Caleb Pitcairn, Joseph R. Mazzulli*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

1 Scopus citations

Abstract

Parkinson’s disease (PD) is a common age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the midbrain. A hallmark of both familial and sporadic PD is the presence of Lewy body inclusions composed mainly of aggregated α-synuclein (α-syn), a presynaptic protein encoded by the SNCA gene. The mechanisms driving the relationship between α-syn accumulation and neurodegeneration are not completely understood, although recent evidence indicates that multiple branches of the proteostasis pathway are simultaneously perturbed when α-syn aberrantly accumulates within neurons. Studies from patient-derived midbrain cultures that develop α-syn pathology through the endogenous expression of PD-causing mutations show that proteostasis disruption occurs at the level of synthesis/folding in the endoplasmic reticulum (ER), downstream ER-Golgi trafficking, and autophagic-lysosomal clearance. Here, we review the fundamentals of protein transport, highlighting the specific steps where α-syn accumulation may intervene and the downstream effects on proteostasis. Current therapeutic efforts are focused on targeting single pathways or proteins, but the multifaceted pathogenic role of α-syn throughout the proteostasis pathway suggests that manipulating several targets simultaneously will provide more effective disease-modifying therapies for PD and other synucleinopathies.

Original languageEnglish (US)
JournalNeuroscientist
DOIs
StateAccepted/In press - 2024

Keywords

  • autophagy
  • Parkinson’s disease
  • protein trafficking
  • synuclein

ASJC Scopus subject areas

  • General Neuroscience
  • Clinical Neurology

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