Impact of fatty acid-binding proteins and dopamine receptors on α-synucleinopathy

Ichiro Kawahata, Kohji Fukunaga

Research output: Contribution to journalReview articlepeer-review

Abstract

An aging society leads to an increased number of patients with cognitive and movement disorders, such as Parkinson's disease and dementia with Lewy bodies. α-Synuclein accumulation in neuronal cells is a pathological hallmark of α-synucleinopathies. Aberrant soluble oligomeric units of α-synuclein are toxic and disrupt neuronal homeostasis. Fatty acids partially regulate α-synuclein accumulation as well as oligomerization, and fatty acid-binding protein (FABP) associates with the α-synuclein aggregates. Heart-type FABP (hFABP, FABP3) is rich in dopaminergic neurons and interacts with dopamine D2 receptors, specifically the long type (D2L), which is abundant in caveolae. We recently demonstrated that mesencephalic neurons require FABP3 and dopamine D2L receptors for the caveolae-mediated α-synuclein uptake. Accumulated α-synuclein gets fibrillized and tightly co-localizes with FABP3 and dopamine D2L receptors, which leads to mitochondrial dysfunction and loss of tyrosine hydroxylase, a rate-limiting enzyme in dopamine production. Furthermore, the inhibition of FABP3 using small-molecule ligands successfully prevents FABP3-induced neurotoxicity. In this review, we focus on the impact of FABP3, dopamine receptors, and other FABP family proteins in the process of α-synuclein propagation and the subsequent aggregate-induced cytotoxicity. We also propose the potential of FABP as a therapeutic target for α-synucleinopathies.

Original languageEnglish
Pages (from-to)248-254
Number of pages7
JournalJournal of Pharmacological Sciences
Volume148
Issue number2
DOIs
Publication statusPublished - 2022 Feb

Keywords

  • Dopamine D receptor
  • Fatty acid-binding protein
  • Mitochondria
  • Parkinson's disease
  • Tyrosine Hydroxylase
  • α-Synucleinopathy

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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