Homozygous NMNAT2 mutation in sisters with polyneuropathy and erythromelalgia

Huppke, Peter; Wegener, Eike; Gilley, Jonathan; Angeletti, Carlo Alberto; Kurth, Ingo; Drenth, Joost P.H.; Stadelmann, Christine; Barrantes‐Freer, Alonso; BruÌˆck, W.; Thiele, Holger; NuÌˆrnberg, P.; GaÌˆrtner, J.; Orsomando, Giuseppe; Coleman, Michael P.

doi:10.1101/610907

Cited by 12 publications

(17 citation statements)

References 32 publications

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“…These data indicate that the location of NAD + synthesis is crucial, and that NMNAT catalytic activity -not a non-enzymatic function [36] -governs this particular phenotype. Interestingly, human disease alleles of NMNAT1 and NMNAT2 have been identified [37][38][39][40][41][42][43], suggesting that subcellular NAD + regulation is similarly compartmentalized and non-redundant in humans.…”

Section: The Location Of Nad + Synthesis Mattersmentioning

confidence: 99%

Location, Location, Location: Compartmentalization of NAD+ Synthesis and Functions in Mammalian Cells

Cambronne

Kraus

2020

Trends in Biochemical Sciences

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The numerous biological roles of NAD + are organized and coordinated via its compartmentalization within cells. The spatial and temporal partitioning of this intermediary metabolite is intrinsic to understanding the impact of NAD + on cellular signaling and metabolism. We review evidence supporting the compartmentalization of steady-state NAD + levels in cells, as well as how the modulation of NAD + synthesis dynamically regulates signaling by controlling subcellular NAD + concentrations. We further discuss potential benefits to the cell of compartmentalizing NAD + , and methods for measuring subcellular NAD + levels. Subcellular Compartmentalization of NAD + Synthesis, Catabolism, and FunctionOxidized nicotinamide adenine dinucleotide (NAD + ) is a metabolic cofactor that plays essential roles in all domains of life. In over a century of research on NAD + , great strides have been made in understanding the synthesis, degradation, and biological functions of NAD + (Box 1, Tables 1 and 2). Recent interest in the biology of NAD + has been driven by a desire to modulate its metabolic and signaling pathways to counteract illnesses stemming from metabolic disorders, tumorigenesis, inflammation, cardiovascular disease, neurodegeneration, and the onset of pathologies associated with advancing age. NAD + -utilizing (see Glossary) enzymes localize to specific subcellular compartments where they execute specific subcellular functions, leading to compartmentalization of NAD + synthesis and functions. The classic example of NAD + compartmentalization is the molecular distinction from its reduced counterpart, NADH, as well as from NADP + and NADPH. These differences are readily discerned in lysates and in vitro. Additional forms of compartmentalization, nevertheless, are not readily distinguishable in these preparations.

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Section: The Location Of Nad + Synthesis Mattersmentioning

confidence: 99%

Location, Location, Location: Compartmentalization of NAD+ Synthesis and Functions in Mammalian Cells

Cambronne

Kraus

2020

Trends in Biochemical Sciences

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“…Additional evidence supportive of a role for SARM1 and the Wallerian degeneration pathway in human disease has come from genome-wide association studies that identified an increased risk of developing ALS at the SARM1 locus [84]. Furthermore, a recent report describing homozygous mutations in NMNAT2 that cause temperature-sensitive partial loss of NMNAT2 function and are responsible for familial erythromelalgia and polyneuropathy [85], links the Wallerian degeneration pathway to human neurological disease.…”

Section: Role Of Sarm1 In Diseasementioning

confidence: 99%

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

Krauss¹,

Bosanac²,

Devraj³

et al. 2020

Trends in Pharmacological Sciences

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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...

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“…Extensive evidence from animal models has implicated NMNAT-sensitive and SARM1-dependent axon degeneration and/or cell death in a variety of neurodegenerative disorders (Conforti et al, 2014; Coleman & Höke, 2020), but knowledge of genetic association with human diseases is more limited. To date, biallelic NMNAT2 loss-of-function (LoF) variants have been associated with two rare polyneuropathies that broadly resemble the corresponding mouse models (Gilley et al, 2013, 2019; Huppke et al, 2019; Lukacs et al, 2019), and NMNAT1 mutations cause photoreceptor loss in LCA via a mechanism involving SARM1 (Sasaki et al, 2020). While no firm association between SARM1 variation and human disease has yet been established, genome wide association studies (GWAS) have linked the SARM1 chromosomal locus, including an intragenic SNP, to sporadic ALS (Fogh et al, 2014; van Rheenen et al, 2016), although whether SARM1 is the causative gene is not known.…”

Section: Introductionmentioning

confidence: 99%

Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

Gilley

Jackson

Pipis

et al. 2021

Preprint

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SARM1, a protein with critical NADase activity, is a central executioner in a conserved programme of axon degeneration. We describe eight rare missense or in-frame microdeletion human SARM1 variant alleles, in patients with amyotrophic lateral sclerosis (ALS), hereditary spastic paraparesis (HSP), or other motor nerve disorders, that alter the SARM1 auto-inhibitory ARM domain and constitutively hyperactivate SARM1 NADase activity. The constitutive NADase activities of six of the variants are at least as high as that of SARM1 lacking the entire ARM domain and greatly exceed the basal activity of wild-type SARM1, even in the presence of nicotinamide mononucleotide (NMN), its physiological activator. This rise in constitutive activity alone is enough to promote neuronal degeneration in response to otherwise non-harmful mild stress. Importantly, we provide evidence that these gain-of-function alleles are enriched in ALS and HSP patients compared to matched individuals without these conditions within ALS and other motor nerve disorder databases. Together, these data suggest these are risk alleles for ALS and other motor nerve disorders. The broad phenotypic heterogeneity and variable age-of-onset in patients with these alleles raises intriguing questions about the pathogenic mechanism of hyperactive SARM1 variants.

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Homozygous NMNAT2 mutation in sisters with polyneuropathy and erythromelalgia

Cited by 12 publications

References 32 publications

Location, Location, Location: Compartmentalization of NAD+ Synthesis and Functions in Mammalian Cells

Location, Location, Location: Compartmentalization of NAD+ Synthesis and Functions in Mammalian Cells

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

Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

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