About

Robert Gordon Kalb, MD, is an Emeritus Professor of Neurology and an Attending Neurologist at the Philadelphia VA Medical Center and the Hospital of the University of Pennsylvania. He is a Board Certified Adult Neurologist with active practice since 1987, specializing in the diagnosis and management of a broad range of neurological disorders, with particular expertise in ALS. His research focuses on activity-dependent development of circuits in the central nervous system and the healthful compensatory responses of cells and organisms to stressful conditions. His laboratory employs cell and molecular biology techniques using genetically manipulated mice, primary neuron tissue culture, and C. elegans to study synaptic activity, circuit development, and neurodegenerative diseases. His work has identified molecular components such as GluA1, SAP97, and their roles in synapse formation, circuit refinement, and neurodegeneration. His research also explores how mutations in proteins like SOD and TDP43 cause neurodegenerative diseases such as ALS and Frontotemporal Dementia, and how re-wiring cellular metabolism can mitigate neuronal damage. His contributions aim to uncover molecular mechanisms underlying neurological disorders and develop novel therapeutic approaches.

Research topics

• Biology
• Neuroscience
• Cell biology
• Medicine
• Chemistry

Selected publications

• Reduction of RAD23A extends lifespan and mitigates pathology in a mouse model of TDP-43 proteinopathy

  Nature Communications · 2026-01-16

  articleOpen accessSenior author

  Protein misfolding and aggregation are cardinal features of neurodegenerative disease (NDD) and they contribute to pathophysiology by both loss-of-function (LOF) and gain-of-function (GOF) mechanisms. This is well exemplified by TDP-43 which aggregates and mislocalizes in several NDDs. The depletion of nuclear TDP-43 leads to reduction in its normal function in RNA metabolism and the cytoplasmic accumulation of TDP-43 leads to aberrant protein homeostasis. A modifier screen found that loss of rad23 suppressed TDP-43 pathology in invertebrate and tissue culture models. Here we show in the TAR4 mouse model of TDP-43 pathology that genetic or antisense oligonucleotide (ASO)-mediated reduction of rad23a confers benefits on survival and behavior, histological hallmarks of disease and reduction of mislocalized and aggregated TDP-43. This results in improved function of the ubiquitin-proteasome system (UPS) and correction of transcriptomic alterations evoked by pathologic TDP-43. RAD23A-dependent remodeling of the insoluble proteome appears to be a key event driving pathology in this model. As TDP-43 pathology is prevalent in both familial and sporadic NDD, targeting RAD23A may have therapeutic potential. Mislocalized and aggregated TDP-43 drives neurodegeneration in several diseases. The current work shows that RAD23A contributes to TDP-43 toxicity by driving pathological re-distribution of key proteins into an insoluble fraction of cells and thereby leading to loss of function phenotypes.

  PublisherOA PDFDOI

• In Vivo Screen of Parkinson’s Disease GWAS Risk Genes Identifies <i>ARIH2</i> as a Novel Regulator of α-Synuclein Toxicity in Dopaminergic Neurons

  Journal of Neuroscience · 2026-02-06

  articleOpen access

  Parkinson's disease (PD) is a late-onset neurodegenerative disease characterized by preferential degeneration of midbrain dopaminergic neurons and α-synuclein–containing Lewy bodies that are found in both familial and sporadic forms. Genome-wide association studies (GWAS) have identified many loci associated with risk of sporadic PD, but their role in PD pathogenesis remains largely unknown. We screened a subset of GWAS genes in Caenorhabditis elegans ( C. elegans ) as potential modulators of α-synuclein–mediated degeneration of dopaminergic neurons. Loss of ari-2 (human ARIH2 ), an E3 ubiquitin ligase, was identified as the strongest suppressor of dopaminergic neurodegeneration in C. elegans. Unbiased proteomics analysis in human-induced pluripotent stem cell-derived dopaminergic neurons revealed novel substrates of ARIH2 including TPPP3, a regulator of microtubule dynamics. Importantly, TPPP3 was required for ARIH2's effects on α-synuclein–induced dopaminergic neurodegeneration. Our studies reveal an unexpected genetic interaction between two PD-linked genes, α-synuclein and ARIH2 , and suggest that inhibition of ARIH2's enzymatic activity may serve as a potential therapeutic approach in PD.

  PublisherOA PDFDOI

• Ubiquitin Proteasome System Components, RAD23A and USP13, Modulate TDP-43 Solubility and Neuronal Toxicity

  Journal of Neuroscience · 2025-12-10 · 1 citations

  articleOpen accessSenior author

  At autopsy, &gt;95% of ALS cases display a redistribution of the essential RNA binding protein TDP-43 from the nucleus into cytoplasmic aggregates. The mislocalization and aggregation of TDP-43 is believed to be a key pathological driver in ALS. Due to its vital role in basic cellular mechanisms, direct depletion of TDP-43 is unlikely to lead to a promising therapy. Therefore, we have explored the utility of identifying genes that modify its mislocalization or aggregation. We have previously shown that loss of rad-23 improves locomotor deficits in TDP-43 Caenorhabditis elegans models of disease and increases the degradation rate of TDP-43 in cellular models. To understand the mechanism through which these protective effects occur, we generated an inducible mutant TDP-43 HEK293 cell line. We find that knockdown of RAD23A reduces insoluble TDP-43 levels in this model and primary rat cortical neurons expressing human TDP-43 A315T . Utilizing a discovery-based proteomics approach, we then explored how loss of RAD23A remodels the proteome. Through this proteomic screen, we identified USP13, a deubiquitinase, as a new potent modifier of TDP-43 induced aggregation and cytotoxicity. We find that knockdown of USP13 reduces the abundance of sarkosyl insoluble mTDP-43 in both our HEK293 model and primary rat neurons, reduces cell death in primary rat motor neurons, and improves locomotor deficits in C. elegans ALS models.

  PublisherOA PDFDOI

• Ubiquitin Proteasome System Components, RAD23A and USP13, Modulate TDP-43 Solubility and Neuronal Toxicity

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-06 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract At autopsy, &gt;95% of ALS cases display a redistribution of the essential RNA binding protein TDP-43 from the nucleus into cytoplasmic aggregates. The mislocalization and aggregation of TDP-43 is believed to be a key pathological driver in ALS. Due to its vital role in basic cellular mechanisms, direct depletion of TDP-43 is unlikely to lead to a promising therapy. Therefore, we have explored the utility of identifying modifier genes that modify its mislocalization or aggregation. We have previously shown that loss of rad-23 improves locomotor deficits in TDP-43 C. elegans models of disease and increases the degradation rate of TDP-43 in cellular models. To understand the mechanism through which these protective effects occur, we generated an inducible mutant TDP-43 HEK293 cell line. We find that knockdown of RAD23A reduces insoluble TDP-43 levels in this model and primary rat cortical neurons expressing human TDP-43 A315T . Utilizing a discovery-based proteomics approach, we then explored how loss of RAD23A remodels the proteome. Through this proteomic screen, we identified USP13, a deubiquitinase, as a new potent modifier of TDP-43 induced aggregation and cytotoxicity. We find that knockdown of USP13 reduces the abundance of sarkosyl insoluble mTDP-43 in both our HEK293 model and primary rat neurons, reduces cell death in primary rat motor neurons, and improves locomotor deficits in C. elegans ALS models. Significance Statement Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease (NDD) with no effective therapies. The mislocalization and aggregation of TAR DNA binding protein 43 (TDP-43) is a key pathological marker of ALS and other NDDs. Due to its vital functions, targeted therapeutic reduction of TDP-43 could be problematic. Here, we have explored the utility of targeting modifier genes. We find that knockdown of two members of the ubiquitin proteasome system, RAD23A and USP13 , enhance TDP-43 solubility and decrease TDP-43 induced neurotoxicity.

  PublisherDOI

• The molecular mechanism of uptake and cell-to-cell transmission of arginine-containing dipeptide repeat proteins

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-28

  preprintOpen accessSenior authorCorresponding

  Abstract Micro-satellite repeat expansion of the 5’ GGGGCC 3’ sequence in the C9orf72 gene is the most common monogenic form of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dipeptide repeat proteins (DPRs) translated from the mutant allele can be detected in postmortem brains of afflicted individuals. The arginine containing peptides, poly-PR and poly-GR, are particularly noxious to cells. Both have been shown to undergo cell-cell transmission, but the underlying mechanisms are not understood. We found rapid internalization and nucleolar localization of bath-applied hemagglutinin (HA) tagged poly-PR with twenty repeats (HA-PR 20 ) in cell lines and neurons. Small molecule and RNAi approaches implicated a temperature-dependent, fluid phase endocytosis mechanism in HA-PR 20 uptake. We sought to identify DPR-related cell surface uptake factors using a high-resolution proximity labeling technique developed in the MacMillan group, termed µMap. DPR-iridium conjugates identified candidate cell-surface proteins which were interrogated in an RNAi screen. Focusing on our strongest candidate, chondroitin sulfate proteoglycan 4 (CSPG4), we showed that cellular uptake of HA-PR 20 is blocked by inhibition of glycosaminoglycan chain synthesis (using drugs or RNAi) and knockdown or ablation of CSPG4 (using RNAi or CRISPR editing). Reduction of CSPG4 protected PR 20 -induced neuronal toxicity. We used a dual reporter system to interrogate in vitro neuron-to-neuron transmission of PR 50 and found that PR 50 synthesized by one neuron readily spread to neighboring neurons. Transmission was significantly reduced when CSPG4 was knocked down. These results suggest CSPG4 is an important factor in poly-PR internalization and transmission and therefore may be a therapeutic target to slow DPR transmission and disease progression. Significance Statement A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is the most common monogenic form of ALS/FTD. This expansion leads to dipeptide repeat protein (DPR) production through non-canonical translation of repeat-containing RNA. DPRs have been shown to transmit between cells, but how this occurs is not well understood. We identified the cell surface protein chondroitin sulfate proteoglycan 4 (CSPG4) as a mediator of the uptake and intercellular spread of toxic arginine-rich DPRs. Targeting CSPG4 may provide a strategy to block DPR transmission and slow disease progression.

  PublisherDOI

• A role for the cholinergic neuron circadian clock in RNA metabolism and mediating neurodegeneration

  Life Science Alliance · 2025-12-04 · 1 citations

  articleOpen accessSenior authorCorresponding

  Circadian clocks are encoded by a transcription-translation feedback loop that aligns physiological processes with the solar cycle. Previous work linking the circadian clock to the regulation of RNA-binding proteins (RBPs) provides a foundation for the vital examination of their mechanistic connections in the context of amyotrophic lateral sclerosis (ALS)-a fatal neurodegenerative disease commonly marked by disrupted RBP function. Here, we reveal that the spinal cord cholinergic neuron rhythmic transcriptome is enriched for genes associated with ALS and other neurodegenerative diseases. We show that there is time-of-day-dependent expression of ALS-linked RBP transcripts and rhythmic alternative splicing of genes involved in microtubule cytoskeleton organization, intracellular trafficking, and synaptic function. Through in silico analysis of RNA sequencing data from sporadic ALS patients, we find that gene expression profiles altered in disease correspond with rhythmic gene networks. Finally, we report that clock disruption through cholinergic neuron-specific deletion of clock activator BMAL1 increases neurodegeneration and drives time-of-day-dependent alternative splicing of RNA processing genes. Our results establish a role for the cholinergic neuron circadian clock in RNA metabolism and mediating neurodegeneration.

  PublisherOA PDFDOI

• A role for the spinal cord cholinergic neuron circadian clock in RNA metabolism and mediating ALS disease phenotypes

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-11 · 2 citations

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Circadian clocks are encoded by a transcription-translation feedback loop that aligns physiological processes with the solar cycle. Previous work linking the circadian clock to the regulation of RNA-binding proteins (RBPs) and alternative splicing provides a foundation for the vital examination of their mechanistic connections in the context of amyotrophic lateral sclerosis (ALS)—a fatal neurodegenerative disease commonly marked by disrupted RBP function. Here, we reveal that the spinal cord cholinergic neuron rhythmic transcriptome is enriched for genes associated with ALS and other neurodegenerative diseases. We show that there is time-of-day-dependent expression of ALS-linked RBP transcripts and rhythmic alternative splicing of genes involved in fundamental neuronal processes, such as microtubule cytoskeleton organization, intracellular trafficking, and synaptic function. We demonstrate clock-dependent expression of ALS-linked RBP Ataxin 2 in this neuronal subtype. Further, through in silico analysis of RNA sequencing data from sporadic ALS patients, we find that gene expression profiles altered in disease correspond with rhythmic gene networks. Finally, we report that clock disruption through cholinergic neuron-specific deletion of clock activator BMAL1 ( i ) increases lumbar spinal cord motor neuron loss and sciatic nerve axon degeneration and ( ii ) drives time-of-day-dependent alternative splicing of genes associated with RNA metabolism, including genes encoding ALS-linked RBPs (e.g., Matr3 , Srsf7 , and Ythdf2 ). Our results establish a role for the cholinergic neuron circadian clock in RNA metabolism and mediating neurodegeneration.

  PublisherOA PDFDOI

• Titin is a nucleolar protein in neurons

  Research Square · 2024-03-04 · 5 citations

  preprintOpen accessSenior author
  PublisherOA PDFDOI

• Reduction of RAD23A extends lifespan and mitigates pathology in TDP-43 mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-09-14 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Protein misfolding and aggregation are cardinal features of neurodegenerative disease (NDD) and they contribute to pathophysiology by both loss-of-function (LOF) and gain-of-function (GOF) mechanisms. This is well exemplified by TDP-43 which aggregates and mislocalizes in several NDDs. The depletion of nuclear TDP-43 leads to reduction in its normal function in RNA metabolism and the cytoplasmic accumulation of TDP-43 leads to aberrant protein homeostasis. A modifier screen found that loss of rad23 suppressed TDP-43 pathology in invertebrate and tissue culture models. Here we show in a mouse model of TDP-43 pathology that genetic or antisense oligonucleotide (ASO)-mediated reduction in rad23a confers benefits on survival and behavior, histological hallmarks of disease and reduction of mislocalized and aggregated TDP-43. This results in improved function of the ubiquitin-proteasome system (UPS) and correction of transcriptomic alterations evoked by pathologic TDP-43. RAD23A-dependent remodeling of the insoluble proteome appears to be a key event driving pathology in this model. As TDP-43 pathology is prevalent in both familial and sporadic NDD, targeting RAD23A may have therapeutic potential.

  PublisherDOI

• Reduction of RAD23A extends lifespan and mitigates pathology in TDP-43 mice

  Research Square · 2024-09-10

  preprintOpen access1st authorCorresponding
  PublisherOA PDFDOI

Recent grants

• NIH Grant R21NS077909

  NIH · $452k · 2014

• Identification of the endogenous ligand of SAP97 PDZ3

  NIH · $459k · 2013–2015

• AMPK, metabolism and ALS

  NIH · $2.3M · 2018–2021

• ERAD genes that suppress neurodegeneration

  NIH · $462k · 2014–2016

• NIH Grant R21NS060754

  NIH · $396k · 2011

Frequent coauthors

• W Slichter

  100 shared

• York Broadway

  American Association For The Advancement of Science

  75 shared

• H. Fisher

  Dalhousie University

  50 shared

• L Agnew

  50 shared

• Christopher J L Murray

  University of Washington

  50 shared

• William H. James

  Puget Sound Educational Service District

  50 shared

• F. R. Cox

  North Carolina State University

  50 shared

• Rachael L. Neve

  Massachusetts General Hospital

  31 shared

Education

• BA, Biology

  Wesleyan University

  1978