Researchers at NYU Langone’s Parekh Center for Interdisciplinary Neurology are focused on four main projects that capitalize on cross-disciplinary collaboration. Each project focuses on commonalities between multiple neurological disorders and strives to build a framework for how the gut microbiome, peripheral immune system, and immune and glial cells in the central nervous system interact at every stage of neurological disorder.

Gut Microbiome as a Mechanism of Drug Resistance in Epilepsy

Principal investigators: Claude Steriade, MD, and Deepak Saxena, MS, PhD

There are an estimated 3.4 million people with active epilepsy in the United States. Despite an exponential increase in approved medications to treat epilepsy, one third of patients remain refractory to medications, and mechanisms of drug resistance are not completely understood.

Drug-resistant epilepsy presents with alterations in the gut microbiome, and ketogenic diet studies have suggested that the gut microbiome influences seizure control. Therefore, manipulation of the gut microbiome may be an effective epilepsy therapy. Seizures are also associated with neuro-inflammation, specifically upregulation of IL1β and IL6, and inflammatory dysregulation itself, such as altered levels of IL1β, can in turn lead to dysbiosis in animal models. Thus, neuroinflammation is a potential mechanism by which seizures may impact gut dysbiosis, and vice versa.

This project is improving our understanding of the independent role of seizures in the gut microbiome and explores neuro-inflammation as a potential mediator of the relationship between seizures and gut dysbiosis. In doing so, it will inform the design of rational and targeted microbiome interventions in the treatment of epilepsy.

Genetic and Cellular Interactions in Familial Dysautonomia and Hirschsprung Disease

Principal investigator: Sumantra Chatterjee, PhD, and Horacio Kaufmann, MD
Collaborator: Maria Alejandra Gonzalez-Duarte Briseno, MD

Familial dysautonomia (FD) is a congenital, sensory, and autonomic nervous system disorder. Familial dysautonomia’s key clinical features include cardiovascular instability, gastrointestinal (GI) tract dysfunction, and autonomic crises. Familial dysautonomia patient autopsy and pathology studies reveal a reduction in enteric neurons in the GI tract, which is also a classic hallmark of Hirschsprung disease (HSCR), a congenital disorder of the enteric nervous system. The primary cause of familial dysautonomia is a single mutation in the gene ELP1, but isolated cases of Hirschsprung disease arise from multiple coding and regulatory variants in genes within a RET gene regulatory network which control enteric nervous system development.

We hypothesize that in patients with FD+HSCR or other GI dysfunction, there are additional mutations in RET and other genes of the gene regulatory network, along with ELP1. These combined mutations lead to disruption of the genetic program that impacts the existing gene regulatory network, leading to GI phenotypes. To detect cellular changes leading to GI phenotypes, we will perform single cell RNA-sequencing in the developing GI tract of mouse models of familial dysautonomia and Hirschsprung disease. In addition, we will perform targeted sequencing of 24 genes of the RET gene regulatory network in human patients to discover new modifier genes which, in the background of an ELP1 mutation, may lead to GI phenotypes observed in familial dysautonomia patients.

Converging Lines of Evidence Between Alzheimer’s Disease and Epilepsy

Principal Investigator: Jayeeta Basu, PhD, and Orrin Devinsky, MD

Converging lines of evidence support that Alzheimer’s disease (AD) and epilepsy share underlying mechanisms: AD patients have an increased risk of seizures, and developing epilepsy while temporal lobe epilepsy (TLE) patients suffer from memory loss and cognitive impairments that mirror AD symptoms. The hippocampus (HC) and entorhinal cortex (EC) are common seizure foci in TLE and are affected early in AD. While these brain regions are extensively studied in rodents, the cellular and circuit organization of human EC-HC network is not well defined. What are the underlying changes at the level of cell types, molecular and synaptic physiological, that disrupt circuit dynamics causing hyperexcitability in TLE and AD?

A critical gap remains in understanding the consequences of seizure activity on HC neurons and circuit dynamics that limits our ability to effectively treat seizures and prevent or reverse cognitive and behavioral comorbidities. In an unprecedented, multidisciplinary collaboration, our study will decipher the synaptic, cellular, and circuit-level mechanisms for neuronal hyperexcitability in human epilepsy patients, and in rodent models of AD prone to epilepsy. By identifying common brain regions and cell-types of vulnerability in TLE and AD, we seek to better understand the mechanisms of epileptogenesis, neurodegeneration, and memory and cognitive dysfunctions, and to identify novel therapeutic targets for early intervention, to prevent or reverse cognitive deficits.

Inhibition of the CAMKK2-AMPK Dyad to Prevent Sleep-Deficit Alzheimer’s Disease Pathogenesis

Principal Investigators: Timothy Cardozo, MD, PhD, Ricardo Osorio, MD, and Thomas Wisniewski, MD

Individuals with sleep problems appear to have nearly double the risk for developing cognitive impairment (CI) or Alzheimer’s Disease (AD) and up to 15% of AD prevalence may be directly attributable to sleep dysfunction. Poor sleep quality and daytime sleepiness have been associated with β-amyloid (Aβ) and tau accumulation in cerebrospinal fluid (CSF). Conversely, Aβ, the pathological hallmark of AD, appears to directly impair sleep and its benefits, which is observable in rodent models of AD.

The CAMKK2-AMPK kinase pathway is over-activated by Aβ42 oligomers (Aβ42o) and triggers activation of several downstream effectors, leading to early loss of excitatory synapses (synaptotoxic effects) in neurons before plaque formation and without compromising neuronal viability. This strongly suggests that synaptotoxicity is an early event in AD progression, triggered by Aβ42o.

Sleep disturbance enhances AMPK phosphorylation and CAMKK2 levels in the brain. Thus, CAMKK2-AMPK, sleep, and AD are linked, suggesting that both Aβ42o and sleep disturbance impose a stress on brain tissues that is responded to deleteriously by the CAMKK2-AMPK pathway. AMPK is ubiquitously expressed by all cells in the body, but CAMKK2 expression is largely restricted to AD relevant regions of the brain, and thus constitutes an ideal drug target. The Cardozo lab developed a small molecule CAMKK2 inhibitor, which has properties suggesting it could be delivered orally and penetrate the brain to have its effects. Thus, this research team is in a unique position to establish a highly innovative, long-term research program into the key signaling pathway controlling the intersection of sleep disturbance and AD.