TY - JOUR
T1 - Impact of fatty acid-binding proteins and dopamine receptors on α-synucleinopathy
AU - Kawahata, Ichiro
AU - Fukunaga, Kohji
N1 - Funding Information:
This work was supported in part by grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan ( KAKENHI 19K07097 ), Kobayashi Foundation, Intelligent Cosmos Academic Foundation , Nishinomiya Basic Research Foundation , and Takeda Science Foundation , and by the Strategic Research Program for Brain Sciences of the Japan Agency for Medical Research and Development, AMED ( JP18dm0107071 , JP19dm0107071 , and JP20dm0107071 ) (K.F.).
Publisher Copyright:
© 2021 The Authors
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
KW - Dopamine D receptor
KW - Fatty acid-binding protein
KW - Mitochondria
KW - Parkinson's disease
KW - Tyrosine Hydroxylase
KW - α-Synucleinopathy
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U2 - 10.1016/j.jphs.2021.12.003
DO - 10.1016/j.jphs.2021.12.003
M3 - Review article
C2 - 35063140
AN - SCOPUS:85121732653
VL - 148
SP - 248
EP - 254
JO - Journal of Pharmacological Sciences
JF - Journal of Pharmacological Sciences
SN - 1347-8648
IS - 2
ER -