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Rescue axonal defects by targeting mitochondrial dynamics in hereditary spastic paraplegias

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Neural Regeneration Research 2019年第4期14卷 574-577页

作者： Yongchao Mou Xue-Jun Li Department of Biomedical Sciences University of Illinois College of Medicine Rockford Department of Bioengineering University of Illinois at Chicago

Impaired axonal development and degeneration underlie debilitating neurodegenerative diseases including hereditary spastic paraplegia, a large group of inherited diseases. Hereditary spastic paraplegia is caused by retrograde degeneration of the long corticospinal tract axons, leading to progressive spasticity and weakness of leg and hip muscles. There are over 70 subtypes with various underlying pathophysiological processes, such as defective vesicular trafficking, lipid metabolism, organelle shaping, axonal transport, and mitochondrial dysfunction. Although hereditary spastic paraplegia consists of various subtypes with different pathological characteristics, defects in mitochondrial morphology and function emerge as one of the common cellular themes in hereditary spastic paraplegia. Mitochondrial morphology and function are remodeled by mitochondrial dynamics regulated by several key fission and fusion mediators. However, the role of mitochondrial dynamics in axonal defects of hereditary spastic paraplegia remains largely unknown. Recently, studies reported perturbed mitochondrial morphology in hereditary spastic paraplegia neurons. Moreover, downregulation of mitochondrial fission regulator dynamin-related protein 1, both pharmacologically and genetically, could rescue axonal outgrowth defects in hereditary spastic paraplegia neurons, providing a potential therapeutic target for treating these hereditary spastic paraplegia. This mini-review will describe the regulation of mitochondrial fission/fusion, the link between mitochondrial dynamics and axonal defects, and the recent progress on the role of mitochondrial dynamics in axonal defects of hereditary spastic paraplegia.

关键词： hereditary spastic paraplegia axonal degeneration mitochondrial dynamics fission fusion dynamin-related protein 1 mitochondrial dysfunction induced pluripotent stem cells

Non-cell autonomous role of astrocytes in axonal degeneration of cortical projection neurons in hereditary spastic paraplegias

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Neural Regeneration Research 2022年第6期17卷 1265-1266页

作者： Xue-Jun Li Department of Biomedical Sciences University of Illinois College of Medicine RockfordRockfordILUSA Department of Bioengineering University of Illinois at ChicagoChicagoILUSA

Impai red axonal deve lopment and degeneration underlie many debilitating diseases,including hereditary spastic paraplegia(HSP).HSPs are a heterogeneous group of neurogenetic disorders characterized by axonopathy of cortical motor neurons(Fink,2006;Blackstone et al.,2010).The axonal degeneration of these cortical projection neurons(PNs)in HSP patients disrupts the signals from brain to spinal motor neurons,leading to muscle weakness and *** the discovery of the first HSP gene(SPAST)in 1999,over 80 distinct genetic loci associated with HSP have been *** the mutations of these divergent genes specifically result in axonal degeneration of cortical PNs remains largely unclear,which contributes to the lack of effective treatment to ameliorate,stop,or reverse axonal defects in HSPs.

关键词： degeneration axonal projection

Modeling axonal defects in hereditary spastic paraplegia with human pluripotent stem cells

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Frontiers in Biology 2016年第5期11卷 339-354页

作者： Kyle R. Denton Chongchong Xu Harsh Shah Xue-Jun Li Department of Neuroscience University of Connecticut Health Center Farmington CT 06030 USA Department of Biomedical Sciences University of Illinois College of Medicine at Rockford IL 61107 USA MD program College of Medicine at Rockford IL 61107 USA MD program College of Medicine at Rockford IL 61107 USA Department of Btoengmeertng University of Illinois at Chicago IL 60607 USA

BACKGROUND： Cortical motor neurons, also known as upper motor neurons, are large projection neurons whose axons convey signals to lower motor neurons to control the muscle movements. Degeneration of cortical motor neuron axons is implicated in several debilitating disorders including hereditary spastic paraplegia （HSP）. Since the discovery of the first HSP gene, SPASTthat encodes spastin, over 70 distinct genetic loci associated with HSP have been identified. How the mutations of these functionally diverse genes result in axonal degeneration and why certain axons are affected in HSP remain largely unknown. The development of induced pluripotent stem cell （iPSC） technology has provided researchers an excellent resource to generate patient-specific human neurons to model human neuropathological processes including axonal defects. METHODS： In this article, we will first review the pathology and pathways affected in the common forms of liSP subtypes by searching the PubMed database. We will then summarize the findings and insights gained from studies using iPSC-based models, and discuss challenges and future directions. RESULTS： HSPs, a heterogeneous group of genetic neurodegenerative disorders, exhibit similar pathological changes that result from retrograde axonal degeneration of cortical motor neurons. Recently, iPSCs have been generated from several common forms of HSP including SPG4, SPG3A, and SPG11 patients. Neurons derived from HSP iPSCs exhibit impaired neurite outgrowth, increased axonal swellings, and reduced axonal transport, recapitulating disease-specific axonal defects. CONCLUSIONS： These patient-derived neurons offer a unique tool to study the pathogenic mechanisms and explore the treatments for rescuing axonal defects in HSP, as well as other diseases involving axonopathy.

关键词： HSP axonal degeneration pluripotent stem cells spastin atlastin-1

Stem cell treatment improves post stroke neurological outcomes:a comparative study in male and female rats

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Stroke & Vascular Neurology 2021年第4期6卷 519-527,I0005-I0010页

作者： Koteswara Rao Nalamolu Bharath Chelluboina Casimir A Fornal Siva Reddy Challa David M Pinson David Z Wang Jeffrey D Klopfenstein Krishna Kumar Veeravalli Cancer Biology and Pharmacology College of MedicineUniversity of IllinoisPeoriaIllinoisUSA Pharmaceutical and Biomedical Sciences California Health Sciences UniversityClovisCaliforniaUSA Neurological Surgery University of Wisconsin-MadisonMadisonWisconsinUSA Health Sciences Education College of MedicineUniversity of IllinoisPeoriaIllinoisUSA Neurology College of MedicineUniversity of IllinoisPeoriaIllinoisUSA Neurology Barrow Neurological InstitutePhoenixArizonaUSA Neurosurgery College of MedicineUniversity of IllinoisPeoriaIllinoisUSA OSF HealthCare illinois Neurological Institute PeoriaIllinoisUSA Pediatrics College of MedicineUniversity of IllinoisPeoriaIllinoisUSA

Background and purpose The therapeutic potential of different stem cells for ischaemic stroke treatment is intriguing and somewhat *** results from our laboratory have demonstrated the potential benefits of human umbilical cord blood-derived mesenchymal stem cells(MSC)in a rodent stroke *** hypothesised that MSC treatment would effectively promote the recovery of sensory and motor function in both males and females,despite any apparent sex differences in post stroke brain *** Transient focal cerebral ischaemia was induced in adult Sprague-Dawley rats by occlusion of the middle cerebral *** the procedure,male and female rats of the untreated group were euthanised 1 day after reperfusion and their brains were used to estimate the resulting infarct volume and tissue *** groups of stroke-induced male and female rats were treated with MSC or vehicle and were subsequently subjected to a battery of standard neurological/neurobehavioral tests(Modified Neurological Severity Score assessment,adhesive tape removal,beam walk and rotarod).The tests were administered at regular intervals(at days 1,3,5,7 and 14)after reperfusion to determine the time course of neurological and functional recovery after *** The infarct volume and extent of swelling of the ischaemic brain were similar in males and *** similar pathological stroke lesions,the clinical manifestations of stroke were more pronounced in males than females,as indicated by the neurological scores and other *** treatment significantly improved the recovery of sensory and motor function in both sexes,and it demonstrated efficacy in both moderate stroke(females)and severe stroke(males).Conclusions Despite sex differences in the severity of post stroke outcomes,MSC treatment promoted the recovery of sensory and motor function in male and female rats,suggesting that it may be a promising treatment for stroke.

关键词： neurological female rats

Implications of MMP-12 in the pathophysiology of ischaemic stroke

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Stroke & Vascular Neurology 2024年第2期9卷 97-107页

作者： Krishna Kumar Veeravalli Cancer Biology and Pharmacology University of Illinois College of Medicine at PeoriaPeoriaIllinoisUSA

This article focuses on the emerging role of matrix metalloproteinase-12(MMP-12)in ischaemic stroke(IS).MMP-12 expression in the brain increases dramatically in animal models of IS,and its suppression reduces brain damage and promotes neurological,sensorimotor and cognitive functional ***,MMP-12 could represent a potential target for the management of *** article provides an overview of MMP-12 upregulation in the brain following IS,its deleterious role in the post-stroke pathogenesis(blood-brain barrier disruption,inflammation,apoptosis and demyelination),possible molecular interactions and mechanistic insights,its involvement in post-ischaemic functional deficits and recovery as well as the limitations,perspectives,challenges and future directions for further *** to testing any MMP-12-targeted therapy in patients with acute IS,additional research is needed to establish the effectiveness of MMP-12 suppression against IS in older animals and in animals with *** article also examines the clinical implications of suppressing MMP-12 alone or in combination with MMP-9 for extending the currently limited tissue plasminogen activator therapy time *** of MMP-12 is expected to have a profound influence on the therapeutic management of IS in the future.

关键词： involvement alone directions

Use of HINTS in the acute vestibular *** Overview

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Stroke & Vascular Neurology 2018年第4期3卷 190-196页

作者： Jorge C Kattah Department of Neurology University of Illinois College of MedicinePeoriaIllinoisUSA

Following the initial description of HINTS to diagnose acute vestibular syndrome(AVS)in 2009,there has been significant interest in the systematic evaluation of HINTs to diagnose stroke and other less common central causes of *** trend increased with availability of the video head impulse test(video-HIT).This article reviews the original papers and discusses the main publications from 2009 to *** authors use video-HIT in the diagnosis of patients with AVS;this paper focuses on the major publications on the topic featuring nystagmus,manual and video-HIT,and skew ***-five papers provide a summary of the last 8 years’application of HINTS,the video-HIT added quantitative information to the early clinical *** research will undoubtedly provide specific combination of abnormalities with high degree of lesion localisation and *** a short time following the original description,neurotologist and neurologists in the evaluation of AVS use the HINTS *** introduction of the video-HIT added greater understanding of the complex interaction between the primary vestibular afferents,brainstem and *** addition,it permits evaluation of the angular vestibulo-ocular reflex in the plane of all six semicircular canals,with accurate peripheral versus central lesion localisation often corroborated by brain imaging.

关键词： AVS video doubt

Does Anesthesiologist-Directed Sedation Afford Superior Deep Cannulation Rates and Procedural Outcomes for ERCP in the Community Setting?

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Open Journal of Gastroenterology 2016年第2期6卷 46-52页

作者： Brad Bowyer Kathy Geissler Robert Barclay Sumeet Tewani James Frakes Nicholas Brown Matthew Houlihan Kunal Patel Andrew Spiel rockford Gastroenterology Associates Rockford IL USA university of illinois college of medicine rockford Rockford IL USA

Aim: To compare outcomes by sedation class in community patients undergoing index endoscopic retrograde cholangiopancreatography (ERCP). Methods: Nineteen hundred sixteen consecutive patients underwent ERCP from May 2005 to May 2011. Eight hundred thirty seven patients were excluded due to prior papillary intervention or attempted ERCP. A total of 1079 patients were included. The 981 patients who underwent gastroenterologist directed sedation (GDS) served as the control population, while the 98 patients who received anesthesiologist directed sedation (ADS) served as the case population. Medical records were analyzed for patient demographics, procedure indication, adverse events, case complexity, procedural failure and sedation failure. Case complexity was defined by the grading system proposed by the working party of the ASGE Quality Committee. Sedation failure was defined by agitation or airway compromise prompting termination of the ERCP. Reasons for procedural failure included surgically altered anatomy, luminal obstruction, and technical failure. Study endpoint was defined as successful deep cannulation of the intended target duct. Results: Demographic distribution did not differ between the GDS and the ADS groups. Cannulation success rates were similar between the two groups, with 89.85% in the GDS group, and 89.58% in the ADS group (P = 0.864). There were no statistical differences between sedation groups in procedural or respiratory adverse events. Technical failure was the predominant basis for deep cannulation failure in both groups. Agitation and airway compromise accounted for deep cannulation failure similarly in both groups. The need for reversal agents was low but similar in both groups. There was no statistical advantage in deep cannulation success rate by complexity grade in either sedation class. Conclusion: Excellent procedural outcomes and low adverse event rates were achieved using GDS, a more accessible and cost-effective method in a community-b

关键词： ERCP Community-Based medicine Conscious Sedation Anesthesiologist-Directed Sedation Gastroenterologist-Directed Sedation

Post-stroke mRNA expression profile of MMPs:effect of genetic deletion of MMP-12

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Stroke & Vascular Neurology 2018年第3期3卷 153-159页

作者： Koteswara Rao Nalamolu Bharath Chelluboina Ian B Magruder Diane N Fru Adithya Mohandass Ishwarya Venkatesh Jeffrey D Klopfenstein David M Pinson Krishna M Boini Krishna Kumar Veeravalli Department of Cancer Biology and Pharmacology University of Illinois College of MedicinePeoriaIllinoisUSA Department of Neurosurgery University of Illinois College of MedicinePeoriaIllinoisUSA Comprehensive Stroke Center Illinois Neurological InstituteOSF HealthCare SystemSaint Francis Medical CenterPeoriaIllinoisUSA Department of Pathology University of Illinois College of MedicinePeoriaIllinoisUSA Department of Pharmacological and Pharmaceutical Sciences College of PharmacyUniversity of HoustonHoustonTexasUSA Department of Neurology University of Illinois College of MedicinePeoriaIllinoisUSA

background and purpose Recent reports from our laboratory demonstrated the post-ischaemic expression profile of various matrix metalloproteinases(MMPs)in rats and the detrimental role of MMP-12 in post-stroke brain *** hypothesise that the post-stroke dysregulation of MMPs is similar across species and that genetic deletion of MMP-12 would not affect the post-stroke expression of other *** tested our hypothesis by determining the pre-ischaemic and post-ischaemic expression profile of MMPs in wild-type and MMP-12 knockout *** Focal cerebral ischaemia was induced in wildtype and MMP-12 knockout mice by middle cerebral artery occlusion procedure by insertion of a monofilament *** hour after ischaemia,reperfusion was initiated by removing the *** day after reperfusion,ischaemic brain tissues from various groups of mice were collected,and total RNA was isolated and subjected to cDNA synthesis followed by PCR *** Although the post-stroke expression profile of MMPs in the ischaemic brain of mice is different from rats,there is a clear species similarity in the expression of MMP-12,which was found to be predominantly upregulated in both ***,the post-stroke induction or inhibition of various MMPs in MMP-12 knockout mice is different from their respective expression profile in wild-type ***,the brain mRNA expression profile of various MMPs in MMP-12 knockout mice under normal conditions is also different to their expression in wild-type *** In the ischaemic brain,MMP-12 upregulates several fold higher than any other *** derived with the genetic deletion of MMP-12 are constitutive and have altered MMP expression profile both under normal and ischaemic conditions.

关键词： MMPs removing hypothesis

Poststroke seizure:optimising its management

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Stroke & Vascular Neurology 2019年第1期4卷 48-56页

作者： Michael Y Xu Department of Neurology OSF Illinois Neurological InstituteUniversity of Illinois College of MedicinePeoriaIllinoisUSA

Seizure after stroke or poststroke seizure (PSS) is a common and very important complication of stroke. It can be divided into early seizure and late seizure, depending on seizure onset time after the stroke. It has been reported that ischaemic and haemorrhagic stroke accounts for about 11% of all adult epilepsy cases and 45% of epilepsy cases over 60 years of age. However, there are no reliable guidelines in clinical practice regarding most of the fundamental issues of PSS management. In recent years there has been an increased interest in the study of PSS which may give clinical practitioners a better picture of how to optimise PSS management. Studies have indicated two peaks in PSS occurrence-the first day and 6-12 months after a stroke. Haemorrhagic stroke, cortical involvement, severity of initial neurological deficit, younger patients (<65 years of age), family history of seizures and certain genetic factors carry a higher risk of PSS. The use of continuous electroencephalogram has demonstrated significant benefits in capturing interictal or ictal abnormalities, especially in cases of non-convulsive seizures and non-convulsive status epilepticus. Current available data indicated that there was no significant difference in antiepileptic efficacy among most of the antiepileptic drugs (AEDs) in PSS. Levetiracetam and lamotrigine are the most studied newer generation AEDs and have the best drug tolerance. The purpose of this review is to summarise the recent advances in PSS research and focus on the most important practice issues of PSS management.

关键词： seizure epilepsy involvement