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

Abstract

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. Axonopathy as a Driver of Disability and Loss of Function in NeurodegenerationNeuronal degeneration is a hallmark of most neurological disorders characterized by progressive disability and loss of function of the CNS and PNS [1,2]. Consequently, the development of neuroprotective approaches is a major goal of current drug discovery efforts. To date, several attempts directed toward developing broad neuroprotective therapies have targeted apoptotic and or excitotoxic mechanisms that are operant in neuronal cell bodies, with little to no success in the clinic [3]. This failure is, in part, attributable to our incomplete understanding of the cellular and molecular events that initiate, propagate, or maintain the neurodegenerative process [4]. An increased understanding of the events that lead to progressive neurodegeneration has implicated axonal dysfunction and damage as an early manifestation of disease pathology [5][6][7]. In many cases, axonopathy (see Glossary) precedes overt degeneration of neuronal cell bodies by months to years, leading eventually to degeneration of the soma through a process of retrograde degeneration, termed 'dying back pathology' [5]. These observations, originating from pathological examination [8,9] and, more recently, from functional imaging in living patients [10], underscore the importance of the axon as a vulnerable compartment that is a distinct subcellular target of disease pathophysiology [6,11,12].Axons require high energy and intense metabolic activity to maintain ionic gradients across the plasma membrane and to sustain optimal neurotransmission. These high bioenergetic demands, which need to be maintained over meter-long axons, contribute to axonal vulnerability. Indeed, mitochondrial dysfunction and disruptions in axonal transport have been implicated in numerous neurodegenerative conditions [2]. Axonopathy has emerged as a major pathophysio...

SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration

“…While NMNAT1 gene replacement is a potential treatment option for LCA9, if SARM1 plays a more general role in retinal degeneration, then using gene therapy to express this dominant negative SARM1 could not only treat LCA9, but also multiple retinal neurodegenerative diseases. In addition, SARM1 is an enzyme and so small molecule enzyme inhibitors would be another attractive treatment modality ( DiAntonio, 2019 ; Krauss et al, 2020 ). These findings demonstrate the utility of dissecting the molecular mechanism of degeneration in diseases of retinal neurodegeneration.…”

“…Hence, photoreceptor neurodegeneration in LCA9 shares a deep mechanistic similarity to the pathological axon degeneration pathway. Since the SARM1 pathway is likely druggable ( DiAntonio, 2019 ; Krauss et al, 2020 ), these findings provide a framework for developing new therapeutic strategies for treating patients with LCA9 and potentially other retinal disorders.…”

SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

“…While NMNAT1 gene replacement is an exciting treatment option for LCA9, if SARM1 plays a more general role in retinal degeneration, then using gene therapy to express this dominant negative SARM1 could not only treat LCA9, but also multiple retinal neurodegenerative diseases. In addition, SARM1 is an enzyme and so small molecule enzyme inhibitors would be another attractive treatment modality 40,41 . These findings demonstrate the utility of dissecting the molecular mechanism of degeneration in diseases of retinal neurodegeneration.…”

“…Hence, photoreceptor neurodegeneration in LCA9 shares a deep mechanistic similarity to the pathological axon degeneration pathway. Since the SARM1 pathway is likely druggable 40,41 , these findings provide a framework for developing new therapeutic strategies for treating patients with LCA9 and potentially other retinal disorders.…”

The Structural Basis for SARM1 Inhibition, and Activation Under Energetic Stress

“…Multiple studies have demonstrated that SARM1 is a key part of a highly conserved axonal death pathway that is activated by nerve injury (17,18). Importantly, recent studies have shown that SARM1 deficiency confers protection against axonal degeneration in several models of neurodegenerative conditions (6,7,19,20), making SARM1 a compelling molecular target for the development of safe and effective pharmacological therapy to protect axons in a variety of axonopathies (8).…”