Collapsin Response-mediator Protein-5 Research Articles

Clinicopathologic Findings in Patients With Paraneoplastic Neuropathies and Antibodies Strongly Associated With Cancer.

Pathologic descriptions of peripheral nerve involvement in paraneoplastic neuropathies are sparse, mostly from autopsies focusing on CNS and dorsal root ganglia tissues. Here, we describe the clinicopathologic features of peripheral nerve biopsies in patients with paraneoplastic neurologic syndromes to expand the currently limited knowledge. Retrospective review of the Mayo Clinic electronic medical record from 1995 to 2022 for patients identified to have subacute onset neuropathy with paraneoplastic antibodies identified in our neuroimmunology laboratory having available nerve biopsies performed at the time of diagnosis. Patients with another cause of neuropathy not linked to their subacute onset were excluded. Nineteen patients met inclusion criteria: 4 with amphiphysin antibodies, 6 with antineuronal nuclear antibody (ANNA)-1 only, 3 with both ANNA-1 and collapsin response-mediator protein 5 (CRMP-5), 2 with ANNA-2, and 4 with CRMP-5 antibodies only. Fifteen biopsies had reduced the density of myelinated nerve fibers-4 with multifocality. Subperineurial edema was present in 17 biopsies. Prominent epineurial perivascular inflammation was present in 3 biopsies, all belonging to patients with a lumbosacral radiculoplexus neuropathy (LRPN) phenotype. Axonal loss, subperineurial edema, and an absence of prominent inflammation are the most common findings in nerve biopsies of patients with paraneoplastic antibodies strongly associated with cancer. The LRPN phenotype was the only subset with inflammatory collections. Paraneoplastic autoantibody testing should be considered in patients with subacute onset neuropathies, with or without interstitial inflammatory findings.

An update on optic neuritis.

Optic neuritis (ON) is the most common cause of subacute optic neuropathy in young adults. Although most cases of optic neuritis (ON) are classified as typical, meaning idiopathic or associated with multiple sclerosis, there is a growing understanding of atypical forms of optic neuritis such as antibody mediated aquaporin-4 (AQP4)-IgG neuromyelitis optica spectrum disorder (NMOSD) and the recently described entity, myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). Differentiating typical ON from atypical ON is important because they have different prognoses and treatments. Findings of atypical ON, including severe vision loss with poor recovery with steroids or steroid dependence, prominent optic disc edema, bilateral vision loss, and childhood or late adult onset, should prompt serologic testing for AQP4-IgG and MOG-IgG. Although the traditional division of typical and atypical ON can be helpful, it should be noted that there can be severe presentations of otherwise typical ON and mild presentations of atypical ON that blur these traditional lines. Rare causes of autoimmune optic neuropathies, such as glial fibrillary acidic protein (GFAP) and collapsin response-mediator protein 5 (CRMP5) autoimmunity also should be considered in patients with bilateral painless optic neuropathy associated with optic disc edema, especially if there are other accompanying suggestive neurologic symptoms/signs. Typical ON usually recovers well without treatment, though recovery may be expedited by steroids. Atypical ON is usually treated with intravenous steroids, and some forms, such as NMOSD, often require plasma exchange for acute attacks and long-term immunosuppressive therapy to prevent relapses. Since treatment is tailored to the cause of the ON, elucidating the etiology of the ON is of the utmost importance.

Peripheral Nerve Pathology in Antibody Positive Paraneoplastic Neurological Syndromes (P11-8.005)

<h3>Objective:</h3> To describe peripheral nerve histopathology in neuropathy patients with paraneoplastic neurological syndromes (PNS) supported by autoantibody testing. <h3>Background:</h3> Rare autopsy cases in PNS suggest an association with shared antigens of misdirected cytotoxic T-cells against cancers and neural tissues. Neuropathy may be the first manifestation but reports of peripheral nerve pathology are limited. We sought to review the pathologic findings within nerve biopsies of patients having neuropathies linked to cancer and high-risk paraneoplastic antibody seropositivity. <h3>Design/Methods:</h3> We retrospectively reviewed the clinical data and nerve biopsy reports of patients presenting with neuropathy and paraneoplastic syndromes reviewing their cancer diagnosis and peripheral onsets. <h3>Results:</h3> Twelve sural nerves and one radial nerve were biopsied from patients with the following antibodies: Amphiphysin (n=6); Antineuronal nuclear antibodies (ANNA)-1 (n=2); ANNA-2 (n=2); Collapsin response mediator protein-5 (CRMP-5) (n=2); and Purkinje cytoplasmic antibody (PCA1) (n=1). Antibody testing occurred typically after biopsy or concurrently, and all patients had subacute onsets. Patients had overlapping involvements: length-dependent neuropathies (n=5), cranial neuropathies (n=1), brachial plexopathy (n=1), multiple mononeuropathies (n=2), and lumbosacral radiculoplexus involvement (n=8). Time to diagnosis was prolonged; commonly after one year. Malignancies were diverse including breast, ovarian, bladder, non-small cell lung cancer, small cell lung cancer, and coexisting colon and breast cancer. Fiber density was reduced in all, with multifocality frequently seen. Perineurial injury was absent, but sub-perineurial edema was common (n=4). Significant inflammation was absent in all but 5 cases, where small to moderate-sized CD45 collections were seen with vessel wall involvement with clinical lumbosacral plexus neuropathy (Amphiphysin (n=2), ANNA-2, and CRMP5) or multiple mononeuropathies (PCA-1). <h3>Conclusions:</h3> The absence of inflammatory infiltrates with reduced fiber density in distal sensory nerve biopsies is common in paraneoplastic neuropathies. A proximal inflammatory process is theorized. Microvessel inflammatory infiltrates with vessel wall involvement also occurs especially among lumbosacral plexopathy phenotypes. <b>Disclosure:</b> Dr. Granger has nothing to disclose. Dr. Rajnauth has nothing to disclose. The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. The institution of Dr. Dubey has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Astellas. The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Argenx. Dr. Dubey has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for AGRIMS. Dr. Dubey has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Advances in Neurology . Dr. Dubey has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Moffit Cancer Center . Dr. Dubey has received research support from Department of Defense . Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Mills has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Mauermann has received research support from IONIS. The institution of Dr. Mauermann has received research support from Alnylam. Dr. Mauermann has received publishing royalties from a publication relating to health care. Dr. Berini has nothing to disclose. Dr. Dyck has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Akcea/Ionis. Dr. Klein has a non-compensated relationship as a Klein with Neurology Journal that is relevant to AAN interests or activities.

A diagnostic conundrum in the time of a pandemic: a subtle, isolated myelopathy. (P10-5.028)

<h3>Objective:</h3> NA <h3>Background:</h3> Anti-CV2/collapsin response-mediator protein 5 (CRMP5) antibodies are considered “high-risk” markers, frequently associating with paraneoplastic syndromes (PNS). <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 44-year-old woman was recovering from a mild case of COVID-19 when she presented with a single episode of urinary retention and a subacute paraparesis with prominent sensory disturbances and girdle-like pain. Since a spinal cord MRI did not show any lesions and EMG did not detect any conduction defects, she refused further examinations and underwent empiric antimicrobial and steroid therapy, along with physical treatment. However, almost two months later she was still suffering from dysesthesia, dysuria, dyschezia and gait disturbance. A second MRI revealed multiple, asymmetric, short-segment lesions in the spinal cord, with persistent contrast-enhancement (despite the previous steroid treatment), but no brain involvement. Cerebrospinal fluid (CSF) analysis and infectious workup were unremarkable, detecting only a slight increase in CSF proteins and a mirror pattern. An extensive screening for autoimmune and paraneoplastic diseases disclosed anti-CV2/CRMP5 antibodies in the serum; however, antibody titer and confirmatory tests were not available at that time and there was no corresponding reactivity in her CSF. After 3 months the antibodies were still present, arguing for a PET scan, which was uneventful. In the meanwhile the woman was treated with IV steroids, followed by a slow oral tapering with gradual but significant improvement. Indeed, after 6 months the MRI showed a diffuse reduction of the spinal cord swelling and T2 signal change, with no contrast enhancement; her neurological exam still remains strikingly normal. <h3>Conclusions:</h3> This remarkable response to immunotherapy, along with the atypical clinical phenotype and radiographic findings (when compared to reported anti-CV2/CRMP-5 myelopathies), argues for an alternative diagnosis, contemplating a post-infectious etiology rather than a PNS. The case also underlines how commercial line blots should always be confirmed by alternative and more reliable techniques. <b>Disclosure:</b> Federica Boso has nothing to disclose. Dr. Giometto has nothing to disclose.

Anti-Neuronal Nuclear Antibody 3 Autoimmunity Targets Dachshund Homolog 1

Objective To identify the autoantigen defined by Anti-Neuronal Nuclear Antibody-type 3 (ANNA3)-IgG and describe the clinical phenotype of seropositive patients. Background ANNA3 was described in 11 patients with multifocal neurological presentations and cancer; its detection is based on the characteristic immunofluorescence staining on mouse tissue sections; ignorance of the antigen's molecular identity has precluded its ready detection in clinical practice. Design/Methods This study was performed at the Mayo Clinic Neuroimmunology Laboratory. The ANNA3-IgG antigen, identified by immunoprecipitation and mass spectrometry as Dachshund-homolog 1 (DACH1), was confirmed by using a commercial DACH1-specific IgG for immunohistochemical colocalization, antigen-specific Western blot, transfected cell-based immunofluorescence, and immune absorption experiments. Clinical data were abstracted from patients' medical records or provided by referring physicians. Results IgG in 32 ANNA3 seropositive patient sera, but in none of 145 controls, bound to DACH1. Clinical information was available for 30 patients (median age, 63.5 years [range, 49-88]; 67% female). Neurological manifestations included neuropathy, 12; cognitive difficulties or encephalitis, 11; ataxia, 8; dysautonomia, 7 (two additionally had diarrhea and esophageal spasm); chorioretinopathy, 1. Clinical improvement was noted in 8 of 11, all treated with immunosuppressants or oncologic treatment. In two patients, the neurological syndrome appeared or worsened during immune checkpoint inhibitor cancer immunotherapy. A neoplasm was found in 27 patients (90%); fourteen were of neuroendocrine lineage. Coexisting neural autoantibodies were detected in 14 patients (47%), and most predicted a neuroendocrine tumor (specific for neuronal intermediate filaments, collapsin response-mediator protein-5, voltage-gated calcium channel [P/Q-type], ANNA1, SOX1, Purkinje-cell cytoplasmic autoantibody type 2/microtubule-associated-protein-1B). Conclusions IgG specific for DACH1 is a serological biomarker of neurological autoimmunity and cancer in patients of middle-age or older. DACH1-IgG is a valuable addition to comprehensive autoimmune and paraneoplastic neural antibody evaluations in clinical practice.

CRMP5 regulates cell proliferation and development of colorectal cancer via MAPK-dependent signaling.

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Collapsin response mediator protein 5 (CRMP5) belongs to a family of five cytosolic proteins that serve a major role in neural development. CRMP5 has been identified as a biomarker of numerous cancer types, including lung cancer and glioblastoma. However, the role of CRMP5 in CRC remains unclear. In the present study, CRMP5 was characterized as a novel biomarker of poor survival in CRC. CRMP5-overexpression in CRC cells promoted cell proliferation and migration while CPMP5-knockdown decreased cell growth and migration. A novel mechanism was uncovered, by which CRMP5 regulates MAPK signaling to drive CRC cell proliferation and development. Furthermore, CRMP5-overexpression induced chemotherapy resistance and tumor recurrence in CRC. Taken together, these results demonstrated the important role of CRMP5 in the development and proliferation of CRC cells and suggested that CRMP5 may be a novel therapeutic target for CRC.

Spastin interacts with CRMP5 to promote spindle organization in mouse oocytes by severing microtubules.

Microtubule-severing protein (MTSP) is critical for the survival of both mitotic and postmitotic cells. However, the study of MTSP during meiosis of mammalian oocytes has not been reported. We found that spastin, a member of the MTSP family, was highly expressed in oocytes and aggregated in spindle microtubules. After knocking down spastin by specific siRNA, the spindle microtubule density of meiotic oocytes decreased significantly. When the oocytes were cultured in vitro, the oocytes lacking spastin showed an obvious maturation disorder. Considering the microtubule-severing activity of spastin, we speculate that spastin on spindles may increase the number of microtubule broken ends by severing the microtubules, therefore playing a nucleating role, promoting spindle assembly and ensuring normal meiosis. In addition, we found the colocalization and interaction of collapsin response mediator protein 5 (CRMP5) and spastin in oocytes. CRMP5 can provide structural support and promote microtubule aggregation, creating transportation routes, and can interact with spastin in the microtubule activity of nerve cells (30). Knocking down CRMP5 may lead to spindle abnormalities and developmental disorders in oocytes. Overexpression of spastin may reverse the abnormal phenotype caused by the deletion of CRMP5. In summary, our data support a model in which the interaction between spastin and CRMP5 promotes the assembly of spindle microtubules in oocytes by controlling microtubule dynamics, therefore ensuring normal meiosis.

Collapsin response mediator protein 5 (CRMP5) modulates susceptibility to chronic social defeat stress in mice.

Collapsin response mediator protein 5 (CRMP5), a member of the CRMP family, is expressed in the brain, particularly in the hippocampus, an area of the brain that can modulate stress responses. Social stress has a well-known detrimental effect on health and can lead to depression, but not all individuals are equally sensitive to stress. To date, researchers have not conclusively determined how social stress increases the susceptibility of the brain to depression. Here, we used the chronic social defeat stress (CSDS) model and observed higher hippocampal CRMP5 expression in stress-susceptible (SS) mice than in control and stress-resilient (RES) mice. A negative correlation was observed between the expression levels of CRMP5 and the social interaction (SI) ratio. Reduced hippocampal CRMP5 expression increased the SI ratio in SS mice, whereas CRMP5 overexpression was sufficient to induce social avoidance behaviors in control mice following exposure to subthreshold social stress induced by lentivirus-based overexpression and inducible tetracycline-on strategies to upregulate CRMP5. Interestingly, increased CRMP5 expression in SS and lenti-CRMP5-treated mice also caused serum corticosterone concentrations to increase. These findings improve our understanding of the potential mechanism by which CRMP5 triggers susceptibility to social stress, and they support the further development of therapeutic agents for the treatment of stress disorders in humans.

Neoplastic Myelopathies.

This article reviews the current classification system of primary spinal cord tumors and explores evolving diagnostic and therapeutic strategies for both primary tumors and metastatic tumors to various compartments of the spinal cord. The 2016 World Health Organization classification system allows for more precise prognostication of and therapy for spinal cord tumors and has identified new entities, such as the diffuse midline glioma, H3 K27M mutant. Whole-exome sequencing reveals that the genetic background of primary glial spinal cord neoplasms differs from that of their intracranial histologic counterparts in ways that can potentially influence therapy. Targeted and immune checkpoint therapies have improved survival for patients with melanoma and lung cancer and have simultaneously produced novel complications by enhancing radiation toxicity in some cases and by facilitating the emergence of novel autoimmune and paraneoplastic syndromes involving the spinal cord, such as neuromyelitis optica spectrum disorder and syndromes associated with anti-Hu and collapsin response mediator protein-5 (CRMP-5) antibodies. These conditions must be distinguished from tumor or infection. Epidural spinal cord compression treatment paradigms have changed with the advent of robotic surgery and advances in radiation therapy. Neoplastic myelopathies subsume a wide spectrum of pathologies. Neoplastic cord involvement may be primary or secondary and may be approached diagnostically by the particular spinal cord compartment localization. Primary spinal cord tumors account for only 2% to 4% of primary central nervous system tumors, ranging from low-grade glial neoplasms to malignant tumors. Metastatic malignancy to the epidural or leptomeningeal spaces is more common than primary cord tumors. Differential diagnoses arising in the course of evaluation for cord tumors include myelopathies related to radiation or chemotherapy and paraneoplastic syndromes, all of which are sources of significant morbidity. Knowledge of genetic syndromes and the biologic behavior of diverse histologies together with selective application of surgery, radiation, and targeted therapies can facilitate diagnosis, minimize surgical morbidity, and prolong quality of life.

Posterior reversible encephalopathy syndrome case report in an untreated, normotensive, ovarian cancer patient in the presence of paraneoplastic antibodies

BackgroundPosterior reversible encephalopathy syndrome (PRES) is a rare neurological condition with many associated risk factors. The presentation varies and consists of seizures, impaired visual acuity or visual field deficits, disorders of consciousness, headaches, confusion and focal neurological deficits. The diagnosis relies on clinical presentation and MRI findings. Treatment and prognosis are related to the underlying etiology.Case presentationWe present a 58-year-old woman with ovarian cancer who developed symptoms and radiologic signs of PRES with no apparent trigger other than a sudden increase in blood pressure for the first time in her life and before any treatment has begun. Antibodies to collapsin response-mediator protein-5 (CRMP-5), a malignancy related paraneoplastic protein, were identified in her CSF.ConclusionsWe present a novel and intriguing association between PRES and antibodies against CRMP-5 which may highlight a new etiology for this condition.

CRMP-5-IgG Antibody: role in the bilateral uveitis with swollen disc

Autoimmunity against collapsin response-mediator protein-5 (anti-CRMP-5) has been associated with ocular inflammation in paraneoplastic syndrome. We present a 59-year-old Caucasian man with optic neuritis and vitreous cells in both eyes (OU), at different stages. Despite the fact that the patient did not have any systemic disease, we suspected a paraneoplastic syndrome and requested CRMP-5-IgG and a mediastinoscopy. After performing the tests, a small cell lung carcinoma was diagnosed. Autoantibody CRMP-5-IgG positivity and optic neuritis combined with vitreous inflammation was defined as a paraneoplastic entity, avoiding vitreous biopsy and allowing us to suspect malignancy before systemic symptoms appeared.

Autoimmune Vestibulocerebellar Syndromes.

Autoimmune disorders affecting the vestibular end organs, vestibular pathways, vestibular nuclei, and vestibulocerebellum are often underrecognized as a cause of chronic dizziness and ataxia. Autoantibodies specific for cell-surface, synaptic, and intracellular neural antigens serve as biomarkers of these disorders. This article describes the epidemiology, clinical presentation, diagnostic considerations, imaging findings, treatment, and prognosis of autoimmune disorders, in which the vestibulocerebellar syndrome is the main or presenting clinical presentation. Antibodies specific for intracellular antigenic targets described in the article are PCA-1 (Purkinje cell cytoplasmic antibody type 1, also known as anti-Yo), ANNA-1 (antinuclear neuronal antibody type 1, also known as anti-Hu), ANNA-2 (antinuclear neuronal antibody type 2, also known as anti-Ri), Ma1/2 (anti-Kelch-like 11/12 antibody), Kelch-like 11, amphiphysin, CV2 (collapsin response 2, also known as collapsin response mediator protein-5 [CRMP5]), VGCC (voltage-gated calcium channel), GAD65 (glutamic acid decarboxylase 65-kDa isoform), AP3B2 (adaptor protein 3B2, also known as anti-Nb), MAP1B (microtubule-associated protein 1B antibody, also known as anti-PCA-2), and neurochondrin antibodies. Antibodies targeting cell-surface or synaptic antigenic targets described in the article include DNER (delta/notchlike epidermal growth factor related receptor; antigen to anti-Tr), CASPR2 (contactin-associated proteinlike 2), septin-5, Homer-3, and mGluR1 (metabotropic glutamate receptor 1). The vestibulocerebellar presentation is largely indistinguishable among these conditions and is characterized by subacute onset of cerebellar symptoms over weeks to months. The diagnosis of autoimmune vestibulocerebellar syndromes is based on a combination of clinical and serological features, with a limited role for neuroimaging. Subtle eye movement abnormalities can be an early feature in many of these disorders, and therefore a meticulous vestibulo-ocular examination is essential for early and correct identification. Cancer occurrence and its type are variable and depend on the autoantibody detected and other cancer risk factors. Treatment comprises immunotherapy and cancer-directed therapy. Acute immunotherapies such as intravenous immunoglobulin, plasma exchange, and steroids are used in the initial phase, and the use of long-term immunosuppression such as rituximab may be necessary in relapsing cases. Outcomes are better if immunotherapy is started early. The neurologic prognosis depends on multiple factors.

Amphiphysin-IgG autoimmune neuropathy: A recognizable clinicopathologic syndrome.

To define the clinicopathologic features of amphiphysin-immunoglobulin G (IgG)-mediated neuropathy. Patients examined at our institution from January 1, 1995, to September 30, 2018, with amphiphysin-IgG by indirect immunofluorescence and Western blot, were reviewed. Their phenotypes were compared to cases of coexisting collapsin response-mediator protein-5 (CRMP5)-IgG or anti-neuronal nuclear antibody type 1 (ANNA1-IgG) and CRMP5-IgG autoimmunity. Improvement in modified Rankin Scale (mRS) (≥1) on follow-up was considered a favorable outcome. Amphiphysin RNA expression was assessed in healthy nerves. Fifty-three amphiphysin-IgG-positive cases were identified. Of 33 (60%) patients with neuropathy, 21 had amphiphysin-IgG alone, and 12 had coexisting autoantibodies (ANNA1-IgG, n = 8; CRMP5-IgG, n = 2; ANNA1-IgG and CRMP5-IgG, n = 2). The neuropathies in isolated amphiphysin-IgG autoimmunity included polyradiculoneuropathy (62%), diffuse sensory neuronopathy (35%), and facial neuropathy with gastroparesis (3%). Among these, pain (80%), breast cancer (63%), and CNS (57%) involvements commonly coexisted, and neuropathy frequently prompted breast cancer diagnosis (76%). Stiff-person spectrum disorder was the most common CNS accompaniment (45%). Nerve biopsies showed axonal loss (n = 6/6), subperineurial edema (n = 4/6), and CD4 predominant inflammation (n = 2/6). Median mRS score at last follow-up was 3.5; 58% of patients were immunotherapy-responsive. Patients with amphiphysin-IgG alone had more favorable immunotherapy response than patients with CRMP5-IgG polyneuropathy (n = 45) (44% vs 16%, p = 0.028, odds ratio 4.2, 95% confidence interval 1.1 to 15.5). Only 1/9 (11%) patients with amphiphysin-IgG with coexisting CRMP5-IgG or ANNA1-IgG had immunotherapy response. RNA amphiphysin expression occurred at low levels in nerve. Amphiphysin-IgG autoimmune neuropathy has a recognizable phenotype, is frequently immune responsive, and can prompt early diagnosis of breast cancer.

Collapsin Response-Mediator Protein 5–Associated Retinitis, Vitritis, and Optic Disc Edema

Collapsin response-mediator protein 5 (CRMP5) immunoglobulin G (IgG) has been associated with paraneoplastic optic neuritis, vitritis, retinitis, or a combination thereof, but few reports of these findings exist in the literature. We reviewed the neuro-ophthalmic findings and visual outcomes in a large series of CRMP5 IgG-positive patients to characterize further its clinical phenotype and response to treatment. Retrospective case series. Seventy-six patients with CRMP5 autoimmunity examined at the Mayo Clinic, Rochester, Minnesota. Single academic medical center chart review of all CRMP5 IgG-positive (serum titer, >1:240) patients seen between 2001 and2017. Neuro-ophthalmic manifestations and outcomes of CRMP5 autoimmunity, coexisting neural autoantibody presence and paraneoplastic associations, and the impact of immunosuppressant therapy. Twenty-nine of 76 patients (38%) demonstrated neuro-ophthalmic manifestations. Of the 29 patients with neuro-ophthalmic findings, the median age was 67 years (range, 33-88 years) and 20 (69%) were women. Cancer was diagnosed in 62% of the patients (small-cell carcinoma in 83%). Neuro-ophthalmic symptoms occurred before the diagnosis of cancer in 72%. Seventeen of 29 patients (59%) showed ocular (i.e., anterior visual pathway or intraocular) manifestations; presenting median visual acuity was 20/50 (range, 20/20-counting fingers) and the final median visual acuity was 20/40 (range, 20/20-hand movements). Fourteen of 17 patients (82%) demonstrated optic neuropathy, with 12 of these patients also showing retinitis or uveitis. Three of 17 patients (18%) showed retinitis or uveitis without optic neuropathy. All 12 patients with optic neuropathy and a documented fundus examination at visual symptom onset demonstrated optic disc edema. No patients showed optic nerve enhancement on magnetic resonance imaging. Twelve of 29 patients (41%) demonstrated ocular motility dysfunction consisting of central nystagmus and diplopia. Among those receiving immunosuppressive therapy, visual function improved in 50%. In our cohort of 29 CRMP5 IgG-positive patients with neuro-ophthalmic manifestations, optic neuropathy presented with optic disc edema, often associated with uveitis, retinitis, or both. The combination of retinitis, vitritis, and optic disc edema without optic nerve enhancement should prompt serologic testing for CRMP5 IgG to expedite vision-sparing immunosuppressant therapy and a targeted search for a systemic cancer.

Collapsin response mediator protein 5 (CRMP5) causes social deficits and accelerates memory loss in an animal model of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by several behavioral disturbances, especially cognitive decline and deficits in social competence. Previous studies revealed that decreased social activity would accelerate AD progression, whereas enhanced social interaction could rescue AD-induced memory impairment. Collapsin response mediator protein 5 (CRMP5), which belongs to a family of cytosolic proteins, is abundantly expressed in the brain and is involved in the regulation of neurodevelopment and the pathology of several neuropsychiatric diseases. However, the functions of CRMP5 in AD are still unclear. Here, we demonstrated that 9-month-old 3xTg-AD mice exhibited social behavioral deficits and increased hippocampal CRMP5 levels compared to control (B6129S) mice. Knockdown of CRMP5 reversed the social deficits in 9-month-old 3xTg-AD mice, whereas CRMP5 overexpression decreased social interaction in both 3xTg-AD and control mice at 6 months of age. Interestingly, decreased expression of CRMP5 rescued AD-induced memory impairment, but overexpression of CRMP5 accelerated memory loss only in 3xTg-AD mice. In addition, we found that CRMP5 could regulate surface GluA2 and GluA2 S880 phosphorylation. These results suggest that CRMP5 regulates social behavior via modulation of surface GluA2 trafficking and affects memory performance in 3xTg-AD mice.

Neuroprotective and neuroregenerative effects of CRMP-5 on retinal ganglion cells in an experimental in vivo and in vitro model of glaucoma.

PurposeTo analyze the potential neuro-protective and neuro-regenerative effects of Collapsin-response-mediator-protein-5 (CRMP-5) on retinal ganglion cells (RGCs) using in vitro and in vivo animal models of glaucoma.MethodsElevated intraocular pressure (IOP) was induced in adult female Sprague-Dawley (SD) rats by cauterization of three episcleral veins. Changes in CRMP-5 expression within the retinal proteome were analyzed via label-free mass spectrometry. In vitro, retinal explants were cultured under elevated pressure (60 mmHg) within a high-pressure incubation chamber with and without addition of different concentrations of CRMP-5 (4 μg/l, 200 μg/l and 400 μg/l). In addition, retinal explants were cultured under regenerative conditions with and without application of 200 μg/l CRMP-5 after performing an optic nerve crush (ONC). Thirdly, an antibody against Protein Kinase B (PKB) was added to examine the possible effects of CRMP-5. RGC count was performed. Number and length of the axons were determined and compared. To undermine a signal-transduction pathway via CRMP-5 and PKB microarray and immunohistochemistry were performed.ResultsCRMP-5 was downregulated threefold in animals showing chronically elevated IOP. The addition of CRMP-5 to retinal culture significantly increased RGC numbers under pressure in a dose-dependent manner and increased and elongated outgrowing axons in retinal explants significantly which could be blocked by PKB. Especially the number of neurites longer than 400 μm significantly increased after application of CRMP-5. CRMP-5 as well as PKB were detected higher in the experimental than in the control group.ConclusionCRMP-5 seems to play an important role in an animal model of glaucoma. Addition of CRMP-5 exerts neuro-protective and neuro-regenerative effects in vitro. This effect could be mediated via activation of PKB affecting intra-cellular apoptosis pathways.

Pharmacological and proteomic analyses of neonatal polyI:C-treated adult mice

Perinatal virus infection is an environmental risk factor for neurodevelopmental disorders such as schizophrenia. We previously demonstrated that neonatal treatment with a viral mimetic, polyriboinosinic-polyribocytidilic acid (polyI:C), in mice leads to emotional and cognitive deficits in adolescence. Here, we investigated the effects of antipsychotics on polyI:C-induced behavioral abnormalities. We also performed a proteomic analysis in the hippocampus of polyI:C-treated adult mice using two-dimensional electrophoresis to understand the changes in protein expression following neonatal immune activation. Neonatal mice were subcutaneously injected with polyI:C for 5 days (postnatal day 2–6). At 10 weeks, sensorimotor gating, emotional and cognitive function were analyzed in behavioral tests. Clozapine improved PPI deficit and emotional and cognitive dysfunction in polyI:C-treated mice. However, haloperidol improved only PPI deficit. Proteomic analysis revealed that two candidate proteins were obtained in the hippocampus of polyI:C-treated mice, including aldehyde dehydrogenase family 1 member L1 (ALDH1L1) and collapsin response mediator protein 5 (CRMP5). These data suggest that the neonatal polyI:C-treated mouse model may be useful for evaluating antipsychotic activity of compounds. Moreover, changes in the protein expression of ALDH1L1 and CRMP5 support our previous findings that astrocyte-neuron interaction plays a role in the pathophysiology of neurodevelopmental disorders induced by neonatal immune activation.

Spastin Interacts with CRMP5 to Promote Neurite Outgrowth by Controlling the Microtubule Dynamics.

Changing the microtubule dynamics is sufficient to alter the axon and dendrite specification and development. Spastin participates in the growth and regeneration of neurites by severing microtubules into small segments, and collapsin response mediator protein 5 (CRMP5) provides structural support and serves as a track for cargo transport by promoting microtubule polymerization. Nevertheless, how spastin and CRMP5 cooperate to regulate neurite outgrowth by controlling the microtubule dynamics needs to be elucidated. In our present study, spastin interacted with CRMP5 in vitro and in vivo. The binding domains for the spastin and CRMP5 interaction were the N-terminal fragment of spastin (residues 270-328) and the C-terminal fragment of CRMP5 (residues 472-564). Spastin and its truncation mutants, including the microtubule-binding domain (MTBD) and ATPases associated with diverse cellular activities (AAA) domain, were necessary for the severing of microtubules. Furthermore, we demonstrated that microtubule polymerization of CRMP5 interfered with the microtubule-severing function of spastin. Knocking down either spastin or CRMP5 inhibited neurite outgrowth in hippocampal neurons. However, co-transfected spastin and CRMP5 promoted the outgrowth of neurites including dendrites and axons. Taken together, our data support a model in which the spastin interaction with CRMP5 promotes neurite outgrowth by controlling the microtubule dynamics.

Clinical Characteristics of CRMP5 Neuropathy

Collapsin response-mediator protein-5 (CRMP5) has been associated with encephalitis, myelopathy, and optic neuritis. To further characterize the

Autoimmune CRMP5 neuropathy phenotype and outcome defined from 105 cases.

To establish the phenotype and clinical outcomes of collapsin response-mediator protein-5 (CRMP5) autoimmune neuropathy in comparison with anti-neuronal nuclear antibody type 1 (ANNA1)-immunoglobulin G (IgG) neuropathy. Patients with CRMP5-IgG and/or ANNA1-IgGs were identified in our service-line testing, and medical records were reviewed. One hundred five patients with CRMP5-IgG neuropathy (88% smokers; 69% having cancer, most commonly small cell lung cancer [75%]) were identified and compared to 51 patients with ANNA1-IgG neuropathy, 27 with coexisting CRMP5-IgG. Patients with CRMP5 had painful axonal polyradiculoneuropathy (65%), mostly asymmetric onset (84%), with neuropathy predating cancer diagnosis by 185 days (range 60-540 days). Most cases (79%) had moderate to severe neuropathic pain, all on neuropathic medications (median 2, range 1-4), opioids in 39%. Nerve biopsies (n = 2) showed microvascular inflammation with axonal degeneration. Compared to ANNA1 alone, CRMP5 neuropathy has a higher prevalence of pain (79% vs 46%, p = 0.008), asymmetric polyradiculoneuropathy (54% vs 12%, p < 0.001), and inflammatory spinal fluids (elevated CSF protein or nucleated cell count 92% vs 60%, p = 0.022). Cerebellar ataxia (21%), myelopathy (19%), and optic neuritis and/or retinitis (11%) were common neurologic accompaniments. CRMP5 cases had significant pain reduction by immunotherapy (p < 0.001). Specifically, high-dose corticosteroid administration was associated with improvement/stabilization in neuropathy impairment scores (p = 0.012) (Class IV). Patients with CRMP5 had better 5-year survival than patients with ANNA1 (67% vs 32%, p = 0.012). Painful axonal asymmetric polyradiculoneuropathy is established as the major CRMP5 autoimmune neuropathy presentation and is distinguishable from other paraneoplastic neuropathies, including by ANNA1 autoimmunity. Patients with this phenotype should be prompted for CRMP5-IgG testing to assist in early cancer diagnosis.