ABCA1: A Therapeutic Target for Improving Cholesterol Homeostasis in Peripheral Neuropathies

ATP-binding cassette A1 (ABCA1) is a critical molecule in facilitating cholesterol transport in a variety of organs. In the nervous system, cholesterol supply is essential and rate-limiting for myelin biogenesis, which underlies efficient conduction of nerve impulses. When myelin is damaged or improperly formed due to genetic defects, a host of neurological symptoms may arise. A rare form of peripheral neuropathy in Tangier disease (TD) patients is associated with autosomal recessive mutations in ABCA1. Accordingly, when ABCA1 loses its function due to misexpression, the neuropathic phenotype is over-represented. Independently, studies have revealed the altered expression of ABCA1 and dysregulation of cholesterol metabolism in a host of inherited peripheral neuropathies engaging the Peripheral Myelin Protein 22 (PMP22), suggesting shared pathophysiology. While the role of ABCA1 has not been investigated broadly in peripheral nerves, the transporter molecule is a therapeutic target for human disorders, including multiple sclerosis and Alzheimer's disease. Investigations in rodent models of type 1 Charcot-Marie-Tooth (CMT) neuropathies support the candidacy of this cholesterol transporter as a therapeutic target in efforts of peripheral myelin repair. Ongoing preclinical studies in central and peripheral nervous system disease models will provide critical information on the importance of ABCA1 as a target for disease modifying intervention.