Chitinases are hydrolytic enzymes responsible for degrading chitin and have been evolutionarily conserved across various species. Although their signaling pathways are not fully understood, the chitinases are considered active immunomodulators across several cell types. Specific isoforms, including Chitotriosidase-1 (CHIT1), Chitinase-3-like protein 1 (CHI3L1), and human-specific Chitinase-3-like protein 2 (CHI3L2), have emerged as markers of inflammation across the neurodegenerative spectrum, including amyotrophic lateral sclerosis (ALS). ALS is a fatal neuromuscular condition, and therapeutic development has been severely hindered by phenotypic heterogeneity and an incomplete understanding of etiology. Although several overlapping disease mechanisms can contribute to neuronal death, inflammation can exacerbate pathology. Prior studies have reported that CHIT1, CHI3L1, and CHI3L2 levels are elevated in the cerebrospinal fluid (CSF) of ALS patients and associated with disease aggressiveness. Nevertheless, several open questions critical to our understanding of the chitinases' role in ALS disease burden remain: namely, 1) which cell types in the central nervous system (CNS) are chitinase sources under physiological conditions, 2) which of these display chitinase upregulation in ALS, and 3) what is the diagnostic utility of the chitinases relative to established biomarkers. Here, we utilize pre-clinical models and post-mortem human tissue to demonstrate at both the transcriptomic and protein level that neurons are a primary source of chitinases; furthermore, neuronal chitinase expression is conserved across species. Under physiological conditions, CHI3L1 is more abundant and widely expressed across various cell types, whereas CHIT1 is predominantly expressed in neurons. Additionally, utilizing symptomatic mice from three familial ALS models, we demonstrate isoform-specific expression profiles, with astroglial and microglial upregulation of CHI3L1, and neuronal and microglial upregulation of CHIT1. Differing expression dynamics and diagnostic utility were also noted in our clinical cohort: CSF CHIT1 and CHI3L2 levels had more discriminatory power when distinguishing between ALS vs. non-ALS controls, while CHI3L1 was more closely associated with inflammation and aging across the neurodegenerative spectrum. Although the chitinases did not diagnostically outperform the neurofilament proteins as biomarkers, we propose that appreciating their expression patterns can aid in optimizing biomarker-guided trial design. Taken together, we demonstrate that chitinase upregulation in ALS is evident in various CNS cell types and that its neuronal expression may provide new insights into its role in disease activity.

Neurodegenerative diseases, such as glaucoma or multiple sclerosis, are characterized by progressive neuronal loss involving diverse pathogenic mechanisms. The brain-derived neurotrophic factor (BDNF) has been implicated in neuroprotection and neural plasticity, yet its regulation and involvement in retinal neurodegenerative diseases remain largely unclear. In this study, we investigated the impact of BDNF deficiency in immune cells on retinal integrity. Using mice with a conditional BDNF knockout in microglia/macrophages and T-cells or selectively in microglia/macrophages, we analyzed retinal changes at 3 and 7 months of age, with wildtype mice as controls. BDNF-deficient mice exhibited early and progressive degeneration of retinal ganglion cells and photoreceptors, accompanied by pronounced astrogliosis, which was exacerbated in aged animals. In 7-month-old mice, adaptive changes in synapses could be documented, evidenced through enhanced expression of the vesicular acetylcholine transporter. These findings demonstrate that BDNF from immune cells plays a crucial role in maintaining retinal homeostasis and that its loss promotes retinal neurodegeneration. Targeting immune cell-derived BDNF may offer novel therapeutic strategies for retinal involvement in neurodegenerative diseases with implications for treatment of glaucoma or multiple sclerosis.

Nociception, the neural process underlying pain detection, is modulated by the NGF/TrkA signaling axis. Although anti-NGF antibodies can alleviate chronic pain, their clinical application is limited by adverse effects, underscoring the need to identify downstream regulators of this pathway. One such mechanism involves TrkA ubiquitination mediated by Nedd4 E3 ubiquitin ligases, whose activity is modulated by Nedd4 family interacting protein 2 (Ndfip2). Notably, Ndfip2 expression is regulated by TrkA signaling under pain conditions. Here, we characterize the physiological and molecular roles of Ndfip2 in sensory neurons. We demonstrate that Ndfip2 localizes to the endoplasmic reticulum and Golgi apparatus and interacts with TrkA in sensory neurons. Conditional deletion of Ndfip2 in TrkA-expressing cells selectively alters mechanical nociception. Mechanistically, loss of Ndfip2 decreases total TrkA protein levels, downstream activation, and cell-surface exposition, particularly in male-derived dorsal root ganglia neurons. Conversely, Ndfip2 expression reduces mature glycosylated TrkA and promotes the accumulation of non-glycosylated forms, consistent with impaired receptor maturation. Together, these findings identify Ndfip2 as a post-translational regulator of TrkA in TrkA-lineage sensory neurons and establish its in vivo role in mechanical nociception.

Degeneration of neuromuscular synapses is a key pathological feature of spinal muscular atrophy (SMA), yet cellular mechanisms underlying synapse dysfunction remain elusive. Here, we show that pharmacological stimulation with Roscovitine triggers the assembly of Munc13-1 release sites that relies on its local translation. Our findings show that presynaptic mRNA levels and local synthesis of Munc13-1 are diminished in motoneurons from SMA mice and hiPSC-derived motoneurons from SMA patients. Replacement of the Munc13-1 3'UTR with that of Synaptophysin1 rescues Munc13-1 mRNA transport in SMA motoneurons and restores the nanoscale architecture of presynaptic Munc13-1 release sites. Restoration of Munc13-1 levels leads to functional synaptic recovery in cultured SMA motoneurons. Furthermore, SMA mice cross-bred with a conditional knock-in mouse expressing modified Munc13-1 with a heterologous 3'UTR display attenuated synapse and neurodegeneration and improved motor function. Identifying Munc13-1 as an SMA modifier underscores the potential of targeting synapses to mitigate neuromuscular dysfunction in SMA.

DYT-THAP1 dystonia is a monogenetic form of dystonia, a movement disorder characterized by the involuntary co-contraction of agonistic and antagonistic muscles. The disease is caused by mutations in the THAP1 gene, although the precise mechanisms by which these mutations contribute to the pathophysiology of dystonia remain unclear. The incomplete penetrance of DYT-THAP1 dystonia, estimated at 40 to 60 %, suggests that an environmental trigger may be required for the manifestation of the disease in genetically predisposed individuals. To investigate the gene-environment interaction in the development of dystonic features, we performed a sciatic nerve crush injury in a genetically predisposed DYT-THAP1 heterozygous knockout mouse model (Thap1+/- ). We employed a multi-omic assessment to study the pathophysiological pathways underlying the disease. Phenotypic analysis using an unbiased deep learning algorithm revealed that nerve-injured Thap1+/- mice exhibited significantly more dystonia like movements (DLM) over the course of the 12-week experiment compared to naive Thap1+/- mice. In contrast, nerve-injured wildtype (wt) mice only showed a significant increase in DLM compared to their naive counterpart during the first weeks after injury. Furthermore, at week 11 after nerve crush, nerve-injured Thap1+/- mice displayed significantly more DLM than nerve-injured wt counterparts. Multi-omic analysis of the cerebellum, striatum and cortex in nerve-injured Thap1+/- mice revealed differences that are indicative of an altered energy metabolism compared to naive Thap1+/- and nerve-injured wt animals. These findings suggest that aberrant energy metabolism in brain regions relevant to dystonia may underlie the dystonic phenotype observed in nerve injured Thap1+/- mice.

Background Chronic arterial hypertension causes cerebral microvascular dysfunction and increases dementia risk in aging. However, cognitive health preservation by therapeutic blood pressure lowering alone is limited and depends on disease duration, the degree of irreversible tissue damage, and whether microvascular function can be restored. This study aimed to understand molecular and cellular temporospatial mechanisms of disease in the course of hypertension. Methods We investigated the effects of initial, early chronic and late chronic hypertension in the frontal brain of spontaneously hypertensive stroke‐prone rats by applying behavioral tests, histopathology, immunofluorescence, fluorescence‐activated cell sorting, microvascular/neural tissue RNA sequencing, and 18 F‐fluorodeoxyglucose positron emission tomography imaging. Results Chronic hypertension caused behavioral deficits associated with frontal cortex function. Our results highlight stage‐dependent responses to continuous microvascular stress and wounding by hypertension. Early chronic responses included a fast recruitment of activated microglia to the blood vessels, immigration of peripheral immune cells, blood–brain barrier breakdown and an energy‐demanding hypermetabolic state. Vascular adaptation mechanisms were observed in later stages and included angiogenesis and upregulation of cellular adhesion molecules and extracellular matrix. Among the top upregulated genes in blood vessels, we identified Igfbp‐5 , which attenuates protective insulin‐like growth factor 1 signaling. Conclusions Our study provides new insight into mechanisms underlying hypertensive pathobiology and highlights its stage‐dependent nature. This groundwork will be helpful for basic and clinical research to identify stage‐dependent markers in the human disease course, investigate stage‐dependent interventions besides blood pressure lowering, and better understand the relationship between poor vascular health and neurodegenerative diseases.

BACKGROUND:Chronic postsurgical inguinal pain (CPIP) is the most common complication of groin hernia surgery. The characteristics of patients, their medical care, and choice of diagnostic tools remain to be defined to optimise preventive and therapeutic interventions. METHODS:Claims data from 2018 and a 1-yr follow-up were analysed for incidence and medical care. A separate cohort (141 healthy controls and 17 CPIP patients) was examined by deep phenotyping. This included sensory testing, blood and skin biopsies, MRI of the dorsal root ganglion (DRG), and patient-reported outcomes. RESULTS:Of 11,221 patients with hernia surgery in 2018 identified, 8.5% had pain before that was relieved by surgery, but a similar percentage had novel pain in this region. Deep phenotyping of 141 healthy controls provided a map of the inguinal sensory system. The following analysis of patients with CPIP revealed that they suffered from moderate pain with neuropathic features, individual sensory abnormalities, and unilateral L1 DRG atrophy. In the blood, levels of C-C-motif chemokine ligand (CCL2) and brain-derived neurotrophic factor (BDNF) were upregulated, whereas apolipoprotein A1 (ApoA1) concentration was reduced. A cluster of DRG atrophy, BDNF, ApoA1, and anxiety correlated best with the diagnosis. CPIP patients with novel pain had significantly more DRG atrophy (-24% ipsilateral vs contralateral volume). CONCLUSIONS:CPIP is often newly acquired after surgery. A combination of DRG imaging, serum markers, and anxiety screening can support the diagnosis. In the future, this could guide clinicians towards more personalised therapies (e.g. targeting anxiety or lipid profiles) and possible altered surgical techniques. CLINICAL TRIAL REGISTRATION:German Trial Registry DRKS00024588 and DRKS00016790.

BACKGROUND AND OBJECTIVES:Patients with autoantibodies (aAbs) against the contactin-associated protein-like 2 (CASPR2) suffer from a variety of clinical syndromes including neuropathic pain. CASPR2 is an adhesion protein of the neurexin family and part of the voltage-gated potassium channel complex (VGKC complex) in dorsal root ganglia (DRG) neurons. The pathologic mechanisms following the binding of CASPR2 aAbs and their association with pain are only partially understood. CASPR2 aAbs are mainly of the IgG4 subclass; however, previous studies have neglected subclass-dependent effects. METHODS:We investigated 49 subclassified patient serum samples positive for CASPR2 aAbs combining superresolution lattice structural illumination microscopy (SIM2) and functional readouts by calcium imaging and electrophysiologic recordings on cultured DRG neurons. CASPR2-positive patient sera subclassified in IgG4 together with at least 1 other IgG subclass (IgGX) and patients with only IgG4 were further subdivided into the pain and no pain groups. RESULTS:A decrease of CASPR2 expression along the axons after exposure to CASPR2 aAbs was observed for all patient groups except the group without pain and IgG4. Moreover, binding of CASPR2 aAbs from patients with pain increased the distance between CASPR2 and associated potassium channels along DRG axons determined by SIM2 microscopy. CASPR2 aAbs of patients with pain significantly increased overall neuronal excitability of cultured DRG neurons as measured by calcium imaging. Patch-clamp recordings revealed significantly decreased current amplitudes of voltage-gated potassium (Kv) channels after incubation with all 4 CASPR2 aAb subclassifications with the most prominent effect of serum samples harboring IgG4 aAbs only. Replacement of patient aAbs by healthy control serum rescued Kv channel function to normal levels suggesting that the affected potassium channel function is due to structural blockage and disrupted interactions within the VGKC complex. The last might also be rescued on novel protein synthesis and membrane trafficking of CASPR2. DISCUSSION:IgG4 aAbs seem to be the major modifier of potassium channel function. The DRG hyperexcitability is primarily due to impaired Kv channel conductance as a consequence of CASPR2 aAb binding. However, additional unidentified signal pathways contribute to this process in patients with neuropathic pain.

Non-invasive delivery of brain therapeutics is a key challenge for treating neurodegenerative diseases. Here, we discovered a novel carboxy (C)-terminal fragment of cerebral dopamine neurotrophic factor (C-CDNF) that protects dopamine (DA) and motoneurons (MNs) in rodent models of Parkinsons disease (PD) and amyotrophic lateral sclerosis (ALS). C-CDNF retains the same structure as CDNF and similarly to CDNF regulates cell stress pathways but unorthodoxly enters cultured neurons and passes through the blood-brain barrier. In vivo, intracranially or peripherally delivered C-CDNF improves motor deficits, protects DA neurons, and restores motor behavior in a rat model of PD. Subcutaneous C-CDNF also protects MNs and reduces microglial activation in an ALS model. Based on our findings, beginning C-CDNF treatment soon after diagnosis is anticipated to delay progression of PD and ALS, thereby improving treatment outcome. Thus, systemic delivery of C-CDNF should simplify the administration of protein-based therapeutics to patients while reducing treatment risk and financial burden for patients and families. ### Competing Interest Statement LY, MA, MS and MHV own the patent rights and are inventors in C-CDNF-related patent applications

Spinal muscular atrophy (SMA) is a devastating neurodegenerative disease characterized by degeneration of spinal motoneurons, leading to muscle atrophy and synaptic loss. SMN functions in mRNA splicing, transport, and local translation are crucial for maintaining synaptic integrity. Within the presynaptic membrane, the active zone orchestrates the docking and priming of synaptic vesicles. The Munc13 family proteins are key active zone components that operate precise neurotransmitter release in conjunction with voltage-gated Ca2+ channels (VGCCs). However, the role of Munc13s in synaptic dysfunction in SMA remains elusive. Our findings reveal that Munc13-1 loss, but not Munc13-2, is closely linked to synaptic aberrations in SMA. Specifically, Munc13-1 mRNA localization in axons is dependent on Smn, and its disruption leads to impaired AZ assembly and VGCC clustering in motoneurons, ultimately reducing neuronal activity. In contrast, Munc13-2 does not appear to be essential for AZ assembly or motoneuron differentiation, as its functions can be compensated by Munc13-1. These findings highlight the pivotal role of Munc13-1 in synapse integrity and point to potential therapeutic targets for mitigating synaptic loss in SMA.

Pathological deposition of hyperphosphorylated tau in the brain closely correlates with the course of Alzheimer’s disease (AD). Tau pathology occurs in axons of affected neurons and tau removal from axons might thus be an early intervention strategy. We investigated the role of the RNA-binding protein hnRNP R in axonal localization and local translation of Mapt mRNA in neurons cultured from hnRNP R knockout mice. hnRNP R knockout mice were crossed with 5×FAD mice, an AD mouse model, and the effects of hnRNP R loss on the deposition of phospho-tau and amyloid-β plaques were evaluated. We designed antisense oligonucleotides (MAPT-ASOs) to block the binding of hnRNP R to Mapt mRNA. Cultured mouse and human neurons were treated with MAPT-ASOs and axonal Mapt mRNA and tau protein levels were quantified. MAPT-ASO was injected intracerebroventricularly into 5×FAD mice followed by quantification of phospho-tau aggregates and amyloid-β plaques in their brains. Protein changes in brains of 5×FAD mice treated with the MAPT-ASO were measured by mass spectrometry. Mapt mRNA and tau protein were reduced in axons but not cell bodies of primary neurons cultured from hnRNP R knockout mice. Brains of 5×FAD mice deficient for hnRNP R contained less phospho-tau aggregates and amyloid-β plaques in the cortex and hippocampus. Treatment of neurons with MAPT-ASOs to block hnRNP R binding to Mapt similarly reduced axonal tau levels. Intracerebroventricular injection of a MAPT-ASO reduced the phospho-tau and plaque load and prevented neurodegeneration in the brains of 5×FAD mice, accompanied by rescue of proteome alterations. Lowering of tau selectively in axons thus represents an innovative therapeutic perspective for treatment of AD and other tauopathies.

Nerve growth factor (NGF) is released after injury from macrophages and other cell types and induces an inflammatory response in neurons, characterized by local subcellular reactions and transcriptomic modulation. NGF-induced axonal transcriptome modulation may be crucial for pain initiation and maintenance. To explore these acute modulations, we cultured dorsal root ganglion neurons in microfluidic chambers and stimulated the axons with NGF. We found that axonal levels of the Il7 transcript encoding interleukin-7 (IL-7) are increased after NGF stimulation, followed by IL-7 release from axons. In growth cones of sensory neurons, we also observed a reorganization of the ribosomal subunits 60S and 40S in response to NGF stimulation. In addition, a dynamic change in the spatio-temporal distribution of the Tropomyosin Kinase B (TrkB) receptor occurs at the plasma membrane of sensory neuron growth cones. TrkB is recruited from the endoplasmic reticulum (ER) leading to increased cell surface levels. De-novo synthesis of TrkB seems to be limited to somatic regions of sensory neurons. Thus, cytosolic mechanisms within distal regions of the sensory neurons may autonomously regulate signaling and translation in response to external NGF stimuli.

Neuropathic pain substantially affects the mental and physical well-being of patients and magnifies the socio-economic burden on the healthcare system. It is important to understand the molecular mechanisms underlying chronic pain to effectively target it. To investigate peripheral mechanisms relevant to pain signalling, we isolated nerve terminals from mouse footpads of wild type and Na V 1.9-deficient mice, which exhibit impaired pain sensation and chronification. The isolated peripheral terminals are functionally active and capable of endocytosis. They contain both pre- and postsynaptic proteins in samples from mice and humans. Components of the protein translational machinery and mitochondria are enriched in nerve terminals, and these components are altered in Na V 1.9 deficient terminals. An unbiased proteomic analysis of nerve terminals from footpads of Na V 1.9 knockout mice shows dysregulation of the mitogen-activated protein kinase and extracellular regulated kinase 1/2 pathways. Preliminary proteomic analysis reveals a strong similarity between mouse and human skin samples, highlighting the broad and translational value of our approach. Our findings uncover peripheral signalling mechanisms involved in nociception, paving the way for unprecedented translational approaches using human biomaterials in pain research.

Background Brain insulin signaling has been associated with both Alzheimer's disease (AD) pathology and cognitive decline, but the mechanisms remain unclear. Objective To examine whether AD-related cortically-expressed proteins modify the association of brain insulin signaling and cognitive decline. Methods Participants included 116 autopsied members of the Religious Orders Study (58 with diabetes matched to 58 without, by age at death, sex, and education) who had both postmortem brain (prefrontal cortex) insulin signaling (by ELISA and immunohistochemistry, including RAC-alpha serine/threonine-protein kinase or AKT1) and AD-related cortical protein measurements. Levels of five AD-related proteins including insulin-like growth factor-binding protein-5 (IGFBP-5) and inositol-tetrakisphosphate 1-kinase (ITPK1) were measured using quantitative proteomics. We conducted adjusted linear mixed model analyses to examine associations of insulin signaling measures and AD-related proteins with longitudinally assessed cognitive function. Results Higher levels of IGFBP-5 and lower levels of ITPK1 were each associated with higher levels of AKT1 phosphorylation (pT 308 AKT1 /total AKT1). Additionally, higher levels of AKT1 phosphorylation were associated with faster decline in global cognition and most cognitive domains. IGFBP-5 partially mediated the association of AKT1 phosphorylation with the decline rate of global cognition and cognitive domains including perceptual speed and visuospatial abilities. Further, ITPK1 had an interaction with AKT1 phosphorylation on decline of global cognition and domains including episodic memory, perceptual speed, and visuospatial abilities. Conclusions AD-related proteins IGFBP-5 and ITPK1 are each associated with insulin signaling AKT1 phosphorylation in the postmortem human brain. Moreover, IGFBP-5 mediates, while ITPK1 moderates, the association between AKT1 phosphorylation and late-life cognitive decline.

Deep brain stimulation (DBS) has emerged as a revolutionary technique for accessing and modulating brain circuits. DBS is used to treat dysfunctional neuronal circuits in neurological and psychiatric disorders. Despite over two decades of clinical application, the fundamental mechanisms underlying DBS are still not well understood. One reason is the complexity of in vivo electrical manipulation of the central nervous system, particularly in rodent models. DBS-devices for freely moving rodents are typically custom-designed and not commercially available, thus making it difficult to perform experimental DBS according to common standards. Addressing these challenges, we have developed a novel wireless microstimulation system for deep brain stimulation (wDBS) tailored for rodents. We demonstrate the efficacy of this device for the restoration of behavioral impairments in hemiparkinsonian mice through unilateral wDBS of the subthalamic nucleus. Moreover, we introduce a standardized and innovative pipeline, integrating machine learning techniques to analyze Parkinson’s disease-like and DBS-induced gait changes.

Increasing evidence suggests an essential function for autophagy in unconventional protein secretion (UPS). However, despite its relevance for the secretion of aggregate-prone proteins, the mechanisms of secretory autophagy in neurons have remained elusive. Here we show that the lower motoneuron disease-associated guanine exchange factor Plekhg5 drives the UPS of Sod1. Mechanistically, Sod1 is sequestered into autophagosomal carriers, which subsequently fuse with secretory lysosomal-related organelles (LROs). Exocytosis of LROs to release Sod1 into the extracellular milieu requires the activation of the small GTPase Rab26 by Plekhg5. Deletion of Plekhg5 in mice leads to the accumulation of Sod1 in LROs at swollen presynaptic sites. A reduced secretion of toxic ALS-linked SOD1(G93A) following deletion of Plekhg5 in SOD1(G93A) mice accelerated disease onset while prolonging survival due to an attenuated microglia activation. Using human iPSC-derived motoneurons we show that reduced levels of PLEKHG5 cause an impaired secretion of ALS-linked SOD1. Our findings highlight an unexpected pathophysiological mechanism that converges two motoneuron disease-associated proteins into a common pathway.

DYT-TOR1A dystonia is the most common monogenic dystonia characterized by involuntary muscle contractions and lack of therapeutic options. Despite some insights into its etiology, the disease's pathophysiology remains unclear. The reduced penetrance of about 30% suggests that extragenetic factors are needed to develop a dystonic phenotype. In order to systematically investigate this hypothesis, we induced a sciatic nerve crush injury in a genetically predisposed DYT-TOR1A mouse model (DYT1KI) to evoke a dystonic phenotype. Subsequently, we employed a multi-omic approach to uncover novel pathophysiological pathways that might be responsible for this condition. Using an unbiased deep-learning-based characterization of the dystonic phenotype showed that nerve-injured DYT1KI animals exhibited significantly more dystonia-like movements (DLM) compared to naive DYT1KI animals. This finding was noticeable as early as two weeks following the surgical procedure. Furthermore, nerve-injured DYT1KI mice displayed significantly more DLM than nerve-injured wildtype (wt) animals starting at 6 weeks post injury. In the cerebellum of nerve-injured wt mice, multi-omic analysis pointed towards regulation in translation related processes. These observations were not made in the cerebellum of nerve-injured DYT1KI mice; instead, they were localized to the cortex and striatum. Our findings indicate a failed translational compensatory mechanisms in the cerebellum of phenotypic DYT1KI mice that exhibit DLM, while translation dysregulations in the cortex and striatum likely promotes the dystonic phenotype.

Tightly regulated cell surface expression of NTRK2/TrkB provides a mechanism for fine-tuning cellular responses to the neurotrophic factor BDNF. Recently, the degradation of NTRK2 by reticulophagy has been identified as a mechanism to limit its availability for trafficking to the cell membrane. The ER-chaperone CANX (calnexin) delivers NTRK2 to the reticulophagy receptor RETREG1/Fam134b for lysosomal degradation. Upon phosphorylation of CANX, NTRK2 is released from this complex, which facilitates its cell surface transport. These results identify a novel role for CANX in regulating the cell surface expression of NTRK2 and imply a function for reticulophagy that goes beyond regulating the degradation of misfolded proteins within the ER.

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations or deletions in the survival motoneuron 1 (SMN1) gene, resulting in deficiency of the SMN protein that is essential for motoneuron function. Smn depletion in mice disturbs axonal RNA transport and translation, thereby contributing to axon growth impairment, muscle denervation, and motoneuron degeneration. However, the mechanisms whereby Smn loss causes axonal defects remain unclear. RNA localization and translation in axons are controlled by RNA-binding proteins (RBP) and we recently observed that the neuronal RBP Ptbp2 modulates axon growth in motoneurons. Here, we identify Smn as an interactor of Ptbp2 in the cytosolic compartments of motoneurons. We show that the expression level of Ptbp2 is reduced in axons but not in the somata of Smn-depleted motoneurons. This is accompanied by reduced synthesis of the RBP hnRNP R in axons. Re-expression of Ptbp2 in axons compensates for the deficiency of Smn and rescues the defects in axon elongation and growth cone maturation observed in Smn-deficient motoneurons. Our data suggest that Ptbp2 and Smn are components of cytosolic mRNP particles, contributing to the precise spatial and temporal control of protein synthesis within axons and axon terminals.