Axons Matter: The Promise of Treating Neurodegenerative Disorders by Targeting SARM1-Mediated Axonal Degeneration

• Published in: Trends in pharmacological sciences (Regular ed.) 2020-04, Vol.41 (4), p.281-293
• Main Authors: Krauss, Raul, Bosanac, Todd, Devraj, Rajesh, Engber, Thomas, Hughes, Robert O.
• Format: Article
• Language: English
• Subjects: Animals; Armadillo Domain Proteins - antagonists & inhibitors; Armadillo Domain Proteins - metabolism; Axonal degeneration; axonopathy; Axons - drug effects; Axons - enzymology; Axons - pathology; Cytoskeletal Proteins - antagonists & inhibitors; Cytoskeletal Proteins - metabolism; Humans; Molecular Targeted Therapy; neurodegeneration; Neurodegenerative Diseases - drug therapy; Neurodegenerative Diseases - enzymology; Neurodegenerative Diseases - pathology; neuropathy; SARM1; Wallerian degeneration
• ISSN: 0165-6147; 1873-3735
• DOI: 10.1016/j.tips.2020.01.006

Attempts to develop neuroprotective treatments for neurodegenerative disorders have not yet been clinically successful. Axonal degeneration has been recognized as a predominant driver of disability and disease progression in central nervous system (CNS) diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, and Parkinson's disease, peripheral nervous system (PNS) disorders such as chemotherapy-induced, diabetic, and inherited neuropathies, and ocular disorders, such as glaucoma. In recent years, sterile alpha and TIR motif containing 1 (SARM1) has emerged as the first compelling axonal-specific target for therapeutic intervention. In this review, we discuss the role of axonal degeneration in neurodegenerative disorders, with a focus on SARM1 and the discovery of its intrinsic enzymatic function. Establishment of neurofilament light chain (NfL) as a reliable biomarker of axonal damage, and the availability of an ultrasensitive method for measuring NfL in plasma or serum, provide translational tools to make development of axonal protective, SARM1 inhibitors a viable approach to treat multiple neurodegenerative disorders. Axonal degeneration is a main contributor to several devastating neurological disorders of the CNS and PNS. Currently, no treatment addresses this pathology.Disease-modifying therapies targeting axonal protection will need to exploit unique aspects of axonal physiology and biochemistry that are distinct from mechanisms operating in the cell body of the neuron.SARM1 is the central mediator of a cell-autonomous molecular program of axonal degeneration in response to injury and stress. It represents a novel and unique therapeutic target with potential to treat a range of neurodegenerative diseases.Recently, NfL emerged as a sensitive translatable biomarker of axonal degeneration and response to treatment in numerous CNS and PNS conditions.The combined availability of SARM1 as a compelling and specific target for axonal protection, and NfL as a translatable clinical biomarker will allow the development of a new class of therapeutics to treat axonopathies.