Macrophage depletion blocks congenital SARM1-dependent neuropathy

Abstract

Axon loss contributes to many common neurodegenerative disorders. In healthy axons, the axon survival factor NMNAT2 inhibits SARM1, the central executioner of programmed axon degeneration.We identified two rare NMNAT2 missense variants in two brothers afflicted with a progressive neuropathy syndrome. The polymorphisms resulted in amino acid substitutions, V98M and R232Q, which reduced NMNAT2 NAD + -synthetase activity. We generated a mouse model of the human syndrome and found that Nmnat2 V98M /Nmnat2 R232Q compound-heterozygous CRISPR mice survived to adulthood but developed progressive motor dysfunction, peripheral axon loss, and macrophage infiltration. These disease phenotypes were all SARM1-dependent. Remarkably, macrophage depletion therapy blocked and reversed neuropathic phenotypes in Nmnat2 V98M/R232Q mice, identifying a SARM1-dependent neuroimmune mechanism as a key driver of disease pathogenesis. These findings demonstrate that SARM1 induces an inflammatory neuropathy and highlight the potential of immune therapy to treat this rare syndrome and other neurodegenerative conditions associated with NMNAT2 loss and SARM1 activation.

A SARM1-mitochondrial feedback loop drives neuropathogenesis in a Charcot-Marie-Tooth disease type 2A rat model

“…If these results hold true in patients, then they have important therapeutic implications, as inhibition of SARM1 would be predicted to dramatically slow disease progression. Both small-molecule and gene therapy SARM1 inhibitors block axon loss in vitro and in vivo ( 15 , 28 , 29 ), and adeno-associated virus–mediated (AAV-mediated) delivery of a SARM1 dominant-negative transgene ameliorates behavioral and pathological phenotypes in another model of a human motor neuropathy ( 21 ).…”

“…Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is an NAD + synthesizing enzyme whose loss results in an increase in nicotinamide mononucleotide (NMN) ( 19 ) and hence an increase in the NMN/NAD + ratio, enabling NMN to displace NAD + from an allosteric binding site in the autoinhibitory domain of SARM1, triggering SARM1 activation ( 20 ). In a mouse model of a human motor neuropathy caused by loss of NMNAT2, SARM1 mediates a slowly progressive motor-predominant neuropathy with axon loss and muscle atrophy ( 21 ), both hallmarks of CMT2A. Finally, genetic variants of SARM1 that encode constitutively active enzymes are enriched in patients with amyotrophic lateral sclerosis (ALS) and other motor neuropathies ( 22 , 23 ).…”

Charcot–Marie–Toothneuropathies: Current gene therapy advances and the route toward translation

“…207 Activation of SARM1 depletes NAD + levels 208 and mediates axonal loss and muscle atrophy. 209 Dominant-negative mutants of SARM1 were packaged into an AAV8 capsid (AAV8-SARM1) and were intrathecally injected (6 Â 10 11 vg) into mice that underwent nerve transection. 47 Treated animals remained intact for more than 10 days after transection, suggesting prevention of trauma-induced axonal degeneration.…”

“…Sterile alpha and Toll/IL1 receptor motif containing 1 (SARM1) protein is a key player of the axonal degeneration pathway 207 . Activation of SARM1 depletes NAD + levels 208 and mediates axonal loss and muscle atrophy 209 . Dominant‐negative mutants of SARM1 were packaged into an AAV8 capsid (AAV8‐ SARM1 ) and were intrathecally injected (6 × 10 11 vg) into mice that underwent nerve transection 47 .…”

Chronically low NMNAT2 expression causes sub-lethal SARM1 activation and altered response to nicotinamide riboside in axons

“…Homozygous partial LOF mutations in NMNAT2 (T94M) were reported in two siblings with childhood onset polyneuropathy and accompanying erythromelalgia that is exacerbated by infection [12]. More recently, two NMNAT2 missense variants (V98M and R232Q, which confer partial and complete LOF respectively), were identified in two brothers with a progressive neuropathy syndrome, who also have erythromelalgia that worsens with infection [13]. Reduced NMNAT2 mRNA levels have also been reported in Parkinson’s, Alzheimer’s and Huntington’s disease patients [14,15].…”