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Northwestern University Feinberg School of Medicine
The Ken & Ruth Davee Department of Neurology
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Neuromuscular Medicine

Below are labs and faculty conducting groundbreaking research on neuromuscular disorders, translating basic science research into new and more effective clinical trials and interventions.

To learn about ongoing clinical trials or participate in a study, visit the clinical trials page for our Division of Neuromuscular Disease.

Labs

 Han-Xiang Deng Lab

The Han-Xiang Deng lab is focused on understanding the mechanism of neurodegenerative diseases such as Amyotrophic Lateral Sclerosis.

Visit Dr. Deng's faculty profile for more information

 Robert Kalb Lab

Activity-dependent development of circuits in the central nervous system and neurodegenerative diseases

Research Description

Glutamatergic synapses that include the GluA1 subunit have a privileged role in activity-dependent brain development and this is driven, in part, through the assembly of a large multi-protein complex in the post-synaptic density. A critical molecular component of this complex is the scaffolding protein SAP97.  Among the >90 known SAP97 binding partners we have determined that a novel protein called CRIPT plays an essential role in this process.  Humans with mutations in CRIPT have a severe developmental brain disorder. We are using a variety of approaches to understand the mechanisms by which CRIPT controls synapse biology and dendrite growth including: 1) study of a conditional knock-out (cKO) mouse that we built, 2) super-resolution imaging of glutamate receptors/TARPs/MAGUKs using neurons derived from patient iPS cells and 3) electrophysiology of dissociated neurons and hippocampal slices from the cKO mice.  Insight into the molecular logic of SAP97/CRIPT function will have implications for childhood maladies such as intellectual disability and autism/autism-spectrum disorders.

In our studies of adult onset neurodegenerative diseases such as Amyotrophic Lateral Sclerosis and Frontotemporal Dementia we find evidence for maladaptive changes in cellular intermediary metabolism and proteostasis.  Ongoing metabolomics interrogations are uncovering why changes in fuel utilization are toxic and discovering new targets for therapeutic intervention.  The relationship between altered metabolism and perturbed protein homeostasis is also an area of intense interest with special focus on a proteasome adaptor protein called RAD23.  Our experimental platforms are: 1) cells from patients with various genetic abnormalities (i.e., mutations in C9orf72, TDP43, etc.) differentiated into neurons, 2) C.elegans, and 3) primary rat/mouse neurons. Targeting proximal events in neurodegenerative diseases will lead to novel therapeutic approaches.

For lab information and more, see Dr. Kalb's faculty profile or the Kalb Lab website.

 

Publications

See Dr. Kalb's publications on PubMed.

Contact

Contact Dr. Kalb at 312-503-5358

 Evangelos Kiskinis Lab

Our laboratory investigates the molecular mechanisms that give rise to neurological diseases using human stem cell-derived neuronal subtypes.

Research Description

The broad objective of our laboratory is to understand the nature of the degenerative processes that drive neurological disease in human patients. We are primarily interested in Amyotrophic Lateral Sclerosis (ALS), Epileptic Syndromes as well as the age-associated changes that take place in the Central Nervous System (CNS). We pursue this objective by creating in vitro models of disease. We utilize patient-specific induced pluripotent stem cells and direct reprogramming methods to generate different neuronal subtypes of the human CNS. We then study these cells by a combination of genomic approaches and functional physiological assays. Our hope is that these disease model systems will help us identify points of effective and targeted therapeutic intervention.

Publications

View Dr. Kiskinis' publications at PubMed

For more information view the faculty profile of Evangelos Kiskinis, PhD, or the Evangelos Kiskinis Lab site.

Contact Information

Evangelos Kiskinis, PhD
Assistant Professor of Neurology

 Daniela Maria Menichella Lab

Our laboratory investigates the molecular and physiological mechanisms underlying neuropathic pain in hereditary and acquired peripheral neuropathies with particular focus on Painful Diabetic Neuropathy (PDN).

Lab Description

PDN is a debilitating affliction present in 26% of diabetic patients with substantial impact on their quality of life. Despite this significant prevalence and impact, current therapies for PDN are only partially effective. Moreover, the molecular and electrophysiological mechanisms underlying neuropathic pain in diabetes are not well understood.

Neuropathic pain is caused by sustained excitability in sensory neurons which reduces the pain threshold, so that pain is produced in the absence of appropriate stimuli. Towards designing more effective therapeutics, our goal is to identify the molecular and physiological mechanisms that shape sustained excitability in sensory neurons responsible for the transition to neuropathic pain in peripheral neuropathies. More specifically we are investigating the role of molecules involved in inflammation such as chemokine and the potential role of microRNAs.

We take advantage of an integrated approach combining pain behavioral tests, electrophysiology studies including current clamp recordings, in vitro and in vivo calcium imaging studies, confocal studies with conditional and transgenic mouse genetic and chemo-genetic silencing of sensory neuron subtypes using mutated hM4D receptor (DREADD) receptors.

Publications

For more publication information see PubMed and for more information see the faculty profile of Daniela Maria Menichella, MD/PhD.

Contact

Daniela Maria Menichella, MD, PhD, at 312-503-3223

 Pembe Hande Ozdinler Lab

Understanding the cortical component of motor neuron circuitry degeneration in ALS and other related disorders.

The Les Turner ALS Laboratory II at Northwestern

Research Description

We are interested in the cellular and molecular mechanisms that are responsible for selective neuronal vulnerability and degeneration in motor neuron diseases. Our laboratory especially focuses on the corticospinal motor neurons (CSMN) which are unique in their ability to collect, integrate, translate and transmit cerebral cortex's input toward spinal cord targets. Their degeneration leads to numerous motor neuron diseases, including amyotrophic lateral sclerosis, hereditary spastic paraplegia and primary lateral sclerosis.

Investigation of CSMN require their visualization and cellular analysis. We therefore, generated reporter lines in which upper motor neurons are intrinsically labeled with eGFP expression. We also characterized progressive CSMN degeneration in various mouse models of motor neuron diseases and continue to generate reporter lines of disease models, in which the upper motor neurons express eGFP.

The overall goal in our investigation, is to develop effective treatment strategies for ALS and other related motor neuron diseases. We appreciate the complexity of the disease and try to focus the problem from three different angles. In one set of studies, we try to reveal the intrinsic factors that could contribute to CSMN vulnerability by investigating the expression profile of more than 40,000 genes and their splice variations at different stages of the disease. In another set of studies, we try to understand the role of non-neuronal cells on motor neuron vulnerability and degeneration, using a triple transgenic mouse model, in which the cells that initiate innate immunity are genetically labeled with fluorescence in an ALS mouse model. These studies will not only reveal the genes that show alternative splice variations, but also inform us on the canonical pathway and networks that are altered with respect to disease initiation and progression.

Even though the above mentioned studies, which use pure populations of neurons and cells isolated by FACS mediated approaches, will reveal the potential mechanisms that are important for CSMN vulnerability, it is important to develop therapeutic interventions. One of the approach we develop is the AAV-mediated gene delivery directly into the CSMN via retrograde transduction. Currently, we are trying to improve CSMN transduction upon direct cortex injection.

Identification of compounds that support CSMN survival is an important component of pre-clinical testing. We develop both in vitro and in vivo compound screening and verification platforms that inform us on the efficiency of compounds for the improvement of CSMN survival.

In summary, we generate new tools and reagents to study the biology of CSMN and to investigate both the intrinsic and extrinsic factors that contribute to their vulnerability and progressive degeneration. We develop compound screening and verification platforms to test their potency on CSMN and develop AAV-mediated gene delivery approaches. Our research will help understand the cellular basis of CSMN degeneration and will help develop novel therapeutic approaches.

For more information see the faculty profile of Pembe Hande Ozdinler, PhD or the Ozdinler Lab website.

Publications

View Dr. Ozdinler's full list of publications at PubMed

Contact

Hande Ozdinler, PhD at 312-503-2774

 Teepu Siddique Lab

We are working to discover causes, understand mechanisms of disease and develop cell and animals model in order to develop rational therapies for neurogenetic and neurodegenerative disorders.
Laboratory of Neurogenetics and Neuromuscular Medicine

Research Description

Our research laboratory is working to determine the causes of and treatments for neurodegenerative disorders and those that affect the muscle, the neuromuscular junction, peripheral nerves and central control of these systems, in particularly those that involve mitochondria and those that involve motor neuron function, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia and ALS (ALS/FTD), primary lateral sclerosis (PLS), the hereditary spastic parapareses (HSP) and related disorders. Recently, we have discovered novel genetic causes of Parkinson Disease. This laboratory has pioneered the gene discovery approach to ALS and related disorders, engineered the first mouse model and have since identified basic molecular mechanisms of pathology in ALS and ALS/dementia on which rational therapy can be now based.

For more information see the faculty profile of Teepu Siddique, MD.

Publications

View Dr. Siddique's full list of publications at PubMed.

Contact Us

Teepu Siddique, MD at 312-503-4737

 Jane Wu Lab

The Wu Laboratory seeks to understand molecular mechanisms regulating gene expression and their involvement in the pathogenesis of age-related diseases, including neurodegeneration and tumor metastasis.

Research Description

RNA Processing and Neurodegeneration

Accumulating evidence supports that aberrant RNA processing represents a general pathogenic mechanism for neurodegeneration, including dementia and amyotrophic lateral sclerosis (ALS). A number of RNA binding proteins (RBPs) have been associated with neurodegenerative diseases, especially various proteinopathies. Recent studies have defined TDP-43 and FUS proteinopathies, a group of heterogeneous neurodegenerative disorders overlapping with dementia, including frontotemporal lobar degeneration (FTLD) and ALS. Several important questions drive our research: what is physiological function of these RBPs? What are the fundamental mechanisms by which genetic mutations in or aberrant regulation of these RBPs cause neural damage? What are the earliest detectable molecular and cellular events that reflect the neural damage in these devastating neurological diseases? How to reverse/repair the neural damage and slow down the progression of these devastating diseases.

To address these questions, we have established cellular and animal models for both TDP-43 and FUS proteinopathies (Li et al, 2010;Barmada et al, 2010; Chen et al, 2011; Fushimi et al, 2011). Using combined biochemical, biophysical, molecular biology and cell biology approaches, we have begun to examine the molecular pathogenic mechanisms underlying neurotoxicity induced by TDP-43 and FUS. Our recent work using atomic force microscopy (AFM), electron microscopy (EM) and (NMR) approaches has shown the biochemical, biophysical and structural similarities between TDP-43 and classical amyloid proteins (Guo et al, 2011; Xu et al, 2013; Bigio et al, 2013). Our study has defined a minimal amyloidogenic region at the carboxyl terminal domain of TDP-43 that is sufficient for amyloid fibril formation and neurotoxicity (Guo et al, 2011; Zhu et al, unpublished). Using cellular and animal models for FUS proteinopathy, we have begun to identify the earliest detectable cellular damage caused by mutations in and overexpression of the human FUS gene. Our data have provided new insights into pathogenic mechanisms underlying these proteinopathies and suggested candidate targets for developing therapeutic approaches.

A critical step in mammalian gene expression is the removal of introns by the process of pre-mRNA splicing. Alternative pre-mRNA splicing, the process of generating multiple mRNA transcripts from a single genetic locus by alternative selection of distinct splice sites, is one of most powerful mechanisms for genetic diversity and an excellent means for fine-tuning gene activity. Many genes critical for neuronal survival and function undergo extensive alternative splicing. Splicing defects play important roles in neurodegenerative disorders such as dementia and motor neuron diseases. For example, splicing mutations in the human tau gene and imbalance of tau splicing isoforms lead to frontotemporal lobar degeneration with tau-positive pathology (FTLD-tau). To understand mechanisms underlying FTLD-tau, we have set up a model system and developed a number of biochemical, molecular and cell biological assays to study alternative splicing of the human tau gene. Our work has led to the identification of a number of cis-elements and trans-acting RBPs controlling tau alternative splicing (Kar et al, 2006; Wu et al, 2006; Kar et al, 2011; Ray et al, 2011). Our experiments have begun to reveal previously unknown players in FTLD-tau and provided new candidate target genes for developing therapeutic strategy (Donahue et al, 2006; unpublished).

Molecular Mechanisms Regulating Axon Guidance, Cell Migration & Tumor Metastasis

Another line of our research focuses on the cellular and molecular mechanisms regulating cell migration and cancer metastasis. Previous studies from our group and others led to the discovery of Slit as a prototype of neuronal guidance cue. Our studies have shown that Slit interacts with Roundabout (Robo) and acts as a chemorepellent for axons and migrating neurons (Wu et al, 1999; Li et al, 1999;Yuasa-Kawada et al, 2009). Our work has demonstrated that Slit-Robo signaling modulates chemokines and inhibits migration of different types of cells, including cancer cells. The observation that Slit is frequently inactivated in a range of tumors suggests an important role of Slit in tumor suppression. We have established several assays and shown that Slit inhibits invasion and migration of cancer cells, including breast cancer, glioma and prostate cancer. We are using combined molecular and cell biology approaches to dissecting Slit-Robo signaling in neuronal guidance and tumor suppression. Our research has provided new insights into signal transduction pathways mediating Slit function. Enhancing or activating the endogenous mechanisms that restrict or suppress cancer invasion/metastasis will likely provide novel approaches to cancer metastasis. 

For more information please view the faculty profile of Jane Wu, MD, PhD or visit the Wu Lab website.

Recent Publications

View a full list of publications by Jane Wu at PubMed

Contact Us

Jane Wu, MD, PhD, at 312-503-0684

 

Faculty

Ajroud-Driss, Senda

Ajroud-Driss, Senda

Associate Professor of Neurology (Neuromuscular Disease)

Bio

Neuromuscular Disorders: Amyotrophic Lateral Sclerosis Muscular Dystropy Peripheral Neuropathy

Brent, Jonathan R

Brent, Jonathan R

Instructor of Neurology (Neuromuscular Disease)

Deng, Han-Xiang

Deng, Han-Xiang

Research Professor of Neurology (Neuromuscular Disease)

Bio

Understanding the mechanism of neurodegenerative diseases such as Amyotrophic Lateral Sclerosis.

Kalb, Robert G

Kalb, Robert G

Professor of Neurology (Neuromuscular Disease)

Kiskinis, Evangelos

Kiskinis, Evangelos

Assistant Professor of Neurology (Neuromuscular Disease) and Physiology

Bio

Our research is focused on addressing fundamental aspects of the biology of human neurons in the context of physiological conditions and in the context of disease. We have two clinical interests, moto... [more]

Menichella, Daniela Maria

Menichella, Daniela Maria

Assistant Professor of Neurology (Neuromuscular Disease) and Pharmacology

Bio

My special interests are focused on peripheral neuropathies, specifically Painful Diabetic Neuropathy, peripheral neuropathies as complication of systemic diseases including rheumatologic conditions, ... [more]

Ozdinler, Pembe Hande

Ozdinler, Pembe Hande

Associate Professor of Neurology (Neuromuscular Disease)

Bio

I am interested in understanding the cellular and molecular mechanisms for cell-type specific degeneration in neurodegenerative diseases. I am mainly focused on corticospinal motor neurons that degene... [more]

Siddique, Teepu

Siddique, Teepu

Professor of Neurology (Neuromuscular Disease), Cell and Developmental Biology and Pathology

Bio

My interest is in understanding mechanism of disease. Our approach is gene discovery, animal and cell culture modeling and therapeutic application in disorders of the nervous system. My specific empha... [more]

Sufit, Robert L

Sufit, Robert L

Professor of Neurology (Neuromuscular Disease) and Surgery (Organ Transplantation)

Bio

Amyotrophic lateral sclerosis, Amyotrophic lateral sclerosis (ALS), Muscular dystrophies, Myasthenia gravis, Neurogenetic disorders, Neuromuscular diseases, Peripheral neuropathies

Tavee, Jinny O

Tavee, Jinny O

Associate Professor of Neurology (Neuromuscular Disease)

Bio

Dr. Tavee is a neuromuscular physician with a special interest in neuropathy, neurosarcoidosis and integrative holistic medicine. In addition to her neuromuscular and sarcoidosis research, she has bee... [more]

Wu, Jane Y

Wu, Jane Y

Professor of Neurology (Neuromuscular Disease)

Bio

My primary research interests are in molecular mechanisms of gene regulation, particularly those involved in neural development and neural degeneration. My lab is focusing on two areas, RNA regulation... [more]

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